Squalene Epoxidase: Its Regulations and Links with Cancers
Abstract
:1. Background
2. The Structure and Topology of SQLE
3. The Role of SQLE in Cholesterol Biosynthesis
4. The Regulation of SQLE
4.1. Regulation by Cholesterol
4.2. Transcriptional Regulation
4.3. Post-Transcriptional Regulation
5. Links with Ferroptosis
6. The Links between SQLE and Cancer
6.1. Colorectal Cancer
6.2. Hepatocellular Carcinoma
6.3. Breast Cancer
6.4. Head and Neck Squamous Cell Carcinoma
6.5. Non-Small Cell Lung Cancer
6.6. Prostate Cancers
6.7. Pancreatic Cancer
6.8. Glioblastoma
6.9. Other Cancers
7. Inhibitors and Clinical Therapeutic Implications
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Duan, Y.; Gong, K.; Xu, S.; Zhang, F.; Meng, X.; Han, J. Regulation of cholesterol homeostasis in health and diseases: From mechanisms to targeted therapeutics. Signal Transduct. Target Ther. 2022, 7, 265. [Google Scholar] [CrossRef] [PubMed]
- Xiao, M.; Xu, J.; Wang, W.; Zhang, B.; Liu, J.; Li, J.; Xu, H.; Zhao, Y.; Yu, X.; Shi, S. Functional significance of cholesterol metabolism in cancer: From threat to treatment. Exp. Mol. Med. 2023, 55, 1982–1995. [Google Scholar] [CrossRef] [PubMed]
- Göbel, A.; Rauner, M.; Hofbauer, L.C.; Rachner, T.D. Cholesterol and beyond—The role of the mevalonate pathway in cancer biology. Biochim. Biophys. Acta Rev. Cancer 2020, 1873, 188351. [Google Scholar] [CrossRef]
- Bloch, K. The biological synthesis of cholesterol. Science 1965, 150, 19–28. [Google Scholar] [CrossRef] [PubMed]
- Luo, J.; Yang, H.; Song, B.-L. Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 2020, 21, 225–245. [Google Scholar] [CrossRef] [PubMed]
- Jiang, W.; Hu, J.-W.; He, X.-R.; Jin, W.-L.; He, X.-Y. Statins: A repurposed drug to fight cancer. J. Exp. Clin. Cancer Res. 2021, 40, 241. [Google Scholar] [CrossRef]
- Gales, L.; Forsea, L.; Mitrea, D.; Stefanica, I.; Stanculescu, I.; Mitrica, R.; Georgescu, M.; Trifanescu, O.; Anghel, R.; Serbanescu, L. Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy. Medicina 2022, 58, 1239. [Google Scholar] [CrossRef] [PubMed]
- Reina-Campos, M.; Heeg, M.; Kennewick, K.; Mathews, I.T.; Galletti, G.; Luna, V.; Nguyen, Q.; Huang, H.; Milner, J.J.; Hu, K.H.; et al. Metabolic programs of T cell tissue residency empower tumour immunity. Nature 2023, 621, 179–187. [Google Scholar] [CrossRef] [PubMed]
- Chua, N.K.; Coates, H.W.; Brown, A.J. Squalene monooxygenase: A journey to the heart of cholesterol synthesis. Prog. Lipid Res. 2020, 79, 101033. [Google Scholar] [CrossRef]
- Cirmena, G.; Franceschelli, P.; Isnaldi, E.; Ferrando, L.; De Mariano, M.; Ballestrero, A.; Zoppoli, G. Squalene epoxidase as a promising metabolic target in cancer treatment. Cancer Lett. 2018, 425, 13–20. [Google Scholar] [CrossRef] [PubMed]
- He, L.; Li, H.; Pan, C.; Hua, Y.; Peng, J.; Zhou, Z.; Zhao, Y.; Lin, M. Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediated MAPK signaling. Cancer Commun. 2021, 41, 726–746. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Wang, Y.; Liu, D.; Wong, C.C.; Coker, O.O.; Zhang, X.; Liu, C.; Zhou, Y.; Liu, Y.; Kang, W.; et al. Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis. Gut 2022, 71, 2253–2265. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Bermudez, J.; Baudrier, L.; Bayraktar, E.C.; Shen, Y.; La, K.; Guarecuco, R.; Yucel, B.; Fiore, D.; Tavora, B.; Freinkman, E.; et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 2019, 567, 118–122. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, K.T.; Mun, S.-H.; Yang, J.; Lee, J.; Seok, O.-H.; Kim, E.; Kim, D.; An, S.Y.; Seo, D.-Y.; Suh, J.-Y.; et al. The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis. Nat. Cell Biol. 2022, 24, 1239–1251. [Google Scholar] [CrossRef]
- Feltrin, S.; Ravera, F.; Traversone, N.; Ferrando, L.; Bedognetti, D.; Ballestrero, A.; Zoppoli, G. Sterol synthesis pathway inhibition as a target for cancer treatment. Cancer Lett. 2020, 493, 19–30. [Google Scholar] [CrossRef] [PubMed]
- Nagai, M.; Sakakibara, J.; Nakamura, Y.; Gejyo, F.; Ono, T. SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase. Biochem. Biophys. Res. Commun. 2002, 295, 74–80. [Google Scholar] [CrossRef]
- Howe, V.; Chua, N.K.; Stevenson, J.; Brown, A.J. The regulatory domain of squalene monooxygenase contains a re-entrant loop and senses cholesterol via a conformational change. J. Biol. Chem. 2015, 290, 27533–27544. [Google Scholar] [CrossRef]
- Chua, N.K.; Howe, V.; Jatana, N.; Thukral, L.; Brown, A.J. A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis. J. Biol. Chem. 2017, 292, 19959–19973. [Google Scholar] [CrossRef] [PubMed]
- Padyana, A.K.; Gross, S.; Jin, L.; Cianchetta, G.; Narayanaswamy, R.; Wang, F.; Wang, R.; Fang, C.; Lv, X.; Biller, S.A.; et al. Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase. Nat. Commun. 2019, 10, 97. [Google Scholar] [CrossRef] [PubMed]
- Gill, S.; Stevenson, J.; Kristiana, I.; Brown, A.J. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase. Cell Metab. 2011, 13, 260–273. [Google Scholar] [CrossRef]
- Brown, A.J.; Chua, N.K.; Yan, N. The shape of human squalene epoxidase expands the arsenal against cancer. Nat. Commun. 2019, 10, 888. [Google Scholar] [CrossRef] [PubMed]
- Sehnal, D.; Bittrich, S.; Deshpande, M.; Svobodová, R.; Berka, K.; Bazgier, V.; Velankar, S.; Burley, S.K.; Koča, J.; Rose, A.S. Mol* Viewer: Modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 2021, 49, W431–W437. [Google Scholar] [CrossRef] [PubMed]
- Burley, S.K.; Bhikadiya, C.; Bi, C.; Bittrich, S.; Chao, H.; Chen, L.; Craig, P.A.; Crichlow, G.V.; Dalenberg, K.; Duarte, J.M.; et al. RCSB Protein Data Bank (RCSB.org): Delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning. Nucleic Acids Res. 2023, 51, D488–D508. [Google Scholar] [CrossRef] [PubMed]
- The UniProt Consortium. UniProt: The universal protein knowledgebase in 2023. Nucleic Acids Res. 2023, 51, D523–D531. [Google Scholar] [CrossRef] [PubMed]
- Chen, F.; Lu, Y.; Lin, J.; Kang, R.; Liu, J. Cholesterol metabolism in cancer and cell death. Antioxid. Redox Signal. 2023, 39, 102–140. [Google Scholar] [CrossRef] [PubMed]
- Broadfield, L.A.; Pane, A.A.; Talebi, A.; Swinnen, J.V.; Fendt, S.-M. Lipid metabolism in cancer: New perspectives and emerging mechanisms. Dev. Cell 2021, 56, 1363–1393. [Google Scholar] [CrossRef] [PubMed]
- Miao, X.; Wang, B.; Chen, K.; Ding, R.; Wu, J.; Pan, Y.; Ji, P.; Ye, B.; Xiang, M. Perspectives of lipid metabolism reprogramming in head and neck squamous cell carcinoma: An overview. Front. Oncol. 2022, 12, 1008361. [Google Scholar] [CrossRef] [PubMed]
- Picón, D.F.; Skouta, R. Unveiling the therapeutic potential of squalene synthase: Deciphering its biochemical mechanism, disease implications, and intriguing ties to ferroptosis. Cancers 2023, 15, 3731. [Google Scholar] [CrossRef] [PubMed]
- Hulce, J.J.; Cognetta, A.B.; Niphakis, M.J.; Tully, S.E.; Cravatt, B.F. Proteome-wide mapping of cholesterol-interacting proteins in mammalian cells. Nat. Methods 2013, 10, 259–264. [Google Scholar] [CrossRef] [PubMed]
- Drin, G.; Antonny, B. Amphipathic helices and membrane curvature. FEBS Lett. 2010, 584, 1840–1847. [Google Scholar] [CrossRef]
- Herlo, R.; Lund, V.K.; Lycas, M.D.; Jansen, A.M.; Khelashvili, G.; Andersen, R.C.; Bhatia, V.; Pedersen, T.S.; Albornoz, P.B.; Johner, N.; et al. An amphipathic helix directs cellular membrane curvature sensing and function of the bar domain protein PICK1. Cell Rep. 2018, 23, 2056–2069. [Google Scholar] [CrossRef] [PubMed]
- Hung, W.-C.; Lee, M.-T.; Chen, F.-Y.; Huang, H.W. The condensing effect of cholesterol in lipid bilayers. Biophys. J. 2007, 92, 3960–3967. [Google Scholar] [CrossRef] [PubMed]
- Kristiana, I.; Luu, W.; Stevenson, J.; Cartland, S.; Jessup, W.; Belani, J.D.; Rychnovsky, S.D.; Brown, A.J. Cholesterol through the Looking Glass. J. Biol. Chem. 2012, 287, 33897–33904. [Google Scholar] [CrossRef] [PubMed]
- Yoshioka, H.; Coates, H.W.; Chua, N.K.; Hashimoto, Y.; Brown, A.J.; Ohgane, K. A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate. Proc. Natl. Acad. Sci. USA 2020, 117, 7150–7158. [Google Scholar] [CrossRef] [PubMed]
- Stevenson, J.; Luu, W.; Kristiana, I.; Brown, A.J. Squalene mono-oxygenase, a key enzyme in cholesterol synthesis, is stabilized by unsaturated fatty acids. Biochem. J. 2014, 461, 435–442. [Google Scholar] [CrossRef] [PubMed]
- Coates, H.W.; Capell-Hattam, I.M.; Olzomer, E.M.; Du, X.; Farrell, R.; Yang, H.; Byrne, F.L.; Brown, A.J. Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase. eLife 2023, 12, e82843. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.; Zhou, S.; Tang, Q.; Xia, H.; Bi, F. Cholesterol metabolism: New functions and therapeutic approaches in cancer. Biochim. Biophys. Acta Rev. Cancer 2020, 1874, 188394. [Google Scholar] [CrossRef]
- Howe, V.; Sharpe, L.J.; Prabhu, A.V.; Brown, A.J. New insights into cellular cholesterol acquisition: Promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2017, 1862, 647–657. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Zhang, H.; Zhang, M.; Lin, C.; Wang, H.; Yao, J.; Wei, Q.; Lu, Y.; Chen, Z.; Xing, G.; et al. OSBPL2 deficiency upregulate SQLE expression increasing intracellular cholesterol and cholesteryl ester by AMPK/SP1 and SREBF2 signalling pathway. Exp. Cell Res. 2019, 383, 111512. [Google Scholar] [CrossRef] [PubMed]
- Zelcer, N.; Sharpe, L.J.; Loregger, A.; Kristiana, I.; Cook, E.C.; Phan, L.; Stevenson, J.; Brown, A.J. The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway. Mol. Cell. Biol. 2014, 34, 1262–1270. [Google Scholar] [CrossRef] [PubMed]
- Tan, J.M.; Cook, E.C.; van den Berg, M.; Scheij, S.; Zelcer, N.; Loregger, A. Differential use of E2 ubiquitin conjugating enzymes for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis. Atherosclerosis 2019, 281, 137–142. [Google Scholar] [CrossRef] [PubMed]
- Chua, N.K.; Scott, N.A.; Brown, A.J. Valosin-containing protein mediates the ERAD of squalene monooxygenase and its cholesterol-responsive degron. Biochem. J. 2019, 476, 2545–2560. [Google Scholar] [CrossRef] [PubMed]
- Chua, N.K.; Hart-Smith, G.; Brown, A.J. Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase. J. Biol. Chem. 2019, 294, 8134–8147. [Google Scholar] [CrossRef] [PubMed]
- Qin, Y.; Zhang, Y.; Tang, Q.; Jin, L.; Chen, Y. SQLE induces epithelial-to-mesenchymal transition by regulating of miR-133b in esophageal squamous cell carcinoma. Acta Biochim. Biophys. Sin. 2017, 49, 138–148. [Google Scholar] [CrossRef] [PubMed]
- Polycarpou-Schwarz, M.; Groß, M.; Mestdagh, P.; Schott, J.; Grund, S.E.; Hildenbrand, C.; Rom, J.; Aulmann, S.; Sinn, H.-P.; Vandesompele, J.; et al. The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. Oncogene 2018, 37, 4750–4768. [Google Scholar] [CrossRef] [PubMed]
- Qin, Y.; Hou, Y.; Liu, S.; Zhu, P.; Wan, X.; Zhao, M.; Peng, M.; Zeng, H.; Li, Q.; Jin, T.; et al. A novel long non-coding RNA lnc030 maintains breast cancer stem cell stemness by stabilizing SQLE mRNA and increasing cholesterol synthesis. Adv. Sci. 2021, 8, 2002232. [Google Scholar] [CrossRef] [PubMed]
- Kalogirou, C.; Linxweiler, J.; Schmucker, P.; Snaebjornsson, M.T.; Schmitz, W.; Wach, S.; Krebs, M.; Hartmann, E.; Puhr, M.; Müller, A.; et al. MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer. Nat. Commun. 2021, 12, 5066. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Chen, J.; Li, Y.; Yang, X.; Wang, Q.; Wen, Y.; Yan, M.; Zhang, J.; Xu, Q.; Wei, Y.; et al. Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma. Cell Death Dis. 2021, 12, 482. [Google Scholar] [CrossRef] [PubMed]
- Sun, H.; Li, L.; Li, W.; Yang, F.; Zhang, Z.; Liu, Z.; Du, W. p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth. EMBO Rep. 2021, 22, e52537. [Google Scholar] [CrossRef] [PubMed]
- Shangguan, X.; Ma, Z.; Yu, M.; Ding, J.; Xue, W.; Qi, J. Squalene epoxidase metabolic dependency is a targetable vulnerability in castration-resistant prostate cancer. Cancer Res. 2022, 82, 3032–3044. [Google Scholar] [CrossRef] [PubMed]
- Ye, Z.; Ai, X.; Yang, K.; Yang, Z.; Fei, F.; Liao, X.; Qiu, Z.; Gimple, R.C.; Yuan, H.; Huang, H.; et al. Targeting microglial metabolic rewiring synergizes with immune-checkpoint blockade therapy for glioblastoma. Cancer Discov. 2023, 13, 974–1001. [Google Scholar] [CrossRef] [PubMed]
- Sharpe, L.J.; Brown, A.J. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase. J. Biol. Chem. 2013, 288, 18707–18715. [Google Scholar] [CrossRef] [PubMed]
- Guan, G.; Jiang, G.; Koch, R.L.; Shechter, I. Molecular cloning and functional analysis of the promoter of the human squalene synthase gene. J. Biol. Chem. 1995, 270, 21958–21965. [Google Scholar] [CrossRef] [PubMed]
- Kawabe, Y.; Sato, R.; Matsumoto, A.; Honda, M.; Wada, Y.; Yazaki, Y.; Endo, A.; Takano, T.; Itakura, H.; Kodama, T. Regulation of fatty acid synthase expression by cholesterol in human cultured cells. Biochem. Biophys. Res. Commun. 1996, 219, 515–520. [Google Scholar] [CrossRef] [PubMed]
- Lopez, J.M.; Bennett, M.K.; Sanchez, H.B.; Rosenfeld, J.M.; Osborne, T.E. Sterol regulation of acetyl coenzyme A carboxylase: A mechanism for coordinate control of cellular lipid. Proc. Natl. Acad. Sci. USA 1996, 93, 1049–1053. [Google Scholar] [CrossRef] [PubMed]
- Ericsson, J.; Jackson, S.M.; Lee, B.C.; Edwards, P.A. Sterol regulatory element binding protein binds to a cis element in the promoter of the farnesyl diphosphate synthase gene. Proc. Natl. Acad. Sci. USA 1996, 93, 945–950. [Google Scholar] [CrossRef] [PubMed]
- Giandomenico, V.; Simonsson, M.; Grünroos, E.; Ericsson, J. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol. Cell. Biol. 2003, 23, 2587–2599. [Google Scholar] [CrossRef]
- Murphy, C.; Ledmyr, H.; Ehrenborg, E.; Gåfvels, M. Promoter analysis of the murine squalene epoxidase gene. Identification of a 205 bp homing region regulated by both SREBP’S and NF-Y. Biochim. Biophys. Acta 2006, 1761, 1213–1227. [Google Scholar] [CrossRef] [PubMed]
- Sundqvist, A.; Ericsson, J. Transcription-dependent degradation controls the stability of the SREBP family of transcription factors. Proc. Natl. Acad. Sci. USA 2003, 100, 13833–13838. [Google Scholar] [CrossRef] [PubMed]
- Jackson, S.M.; Ericsson, J.; Osborne, T.F.; Edwards, P.A. NF-Y has a novel role in sterol-dependent transcription of two cholesterogenic genes. J. Biol. Chem. 1995, 270, 21445–21448. [Google Scholar] [CrossRef] [PubMed]
- Ericsson, J.; Usheva, A.; Edwards, P.A. YY1 is a negative regulator of transcription of three sterol regulatory element-binding protein-responsive genes. J. Biol. Chem. 1999, 274, 14508–14513. [Google Scholar] [CrossRef] [PubMed]
- Zerenturk, E.J.; Sharpe, L.J.; Brown, A.J. Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: Cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins. Biochim. Biophys. Acta 2012, 1821, 1350–1360. [Google Scholar] [CrossRef] [PubMed]
- Van den Boomen, D.J.; Volkmar, N.; Lehner, P.J. Ubiquitin-mediated regulation of sterol homeostasis. Curr. Opin. Cell Biol. 2020, 65, 103–111. [Google Scholar] [CrossRef]
- Tan, J.M.E.; van der Stoel, M.M.; van den Berg, M.; van Loon, N.M.; Moeton, M.; Scholl, E.; van der Wel, N.N.; Kovačević, I.; Hordijk, P.L.; Loregger, A.; et al. The MARCH6-SQLE axis controls endothelial cholesterol homeostasis and angiogenic sprouting. Cell Rep. 2020, 32, 107944. [Google Scholar] [CrossRef] [PubMed]
- Scott, N.A.; Sharpe, L.J.; Brown, A.J. The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2021, 1866, 158837. [Google Scholar] [CrossRef] [PubMed]
- Mun, S.-H.; Lee, C.-S.; Kim, H.J.; Kim, J.; Lee, H.; Yang, J.; Im, S.-H.; Kim, J.-H.; Seong, J.K.; Hwang, C.-S. Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons. Cell Rep. 2023, 42, 112746. [Google Scholar] [CrossRef]
- Zattas, D.; Berk, J.M.; Kreft, S.G.; Hochstrasser, M. A conserved C-terminal element in the yeast Doa10 and human MARCH6 ubiquitin ligases required for selective substrate degradation. J. Biol. Chem. 2016, 291, 12105–12118. [Google Scholar] [CrossRef] [PubMed]
- Kreft, S.G.; Wang, L.; Hochstrasser, M. Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J. Biol. Chem. 2006, 281, 4646–4653. [Google Scholar] [CrossRef]
- Hassink, G.; Kikkert, M.; Van Voorden, S.; Lee, S.-J.; Spaapen, R.; van Laar, T.; Coleman, C.S.; Bartee, E.; Früh, K.; Chau, V.; et al. TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem. J. 2005, 388, 647–655. [Google Scholar] [CrossRef] [PubMed]
- Sharpe, L.J.; Howe, V.; Scott, N.A.; Luu, W.; Phan, L.; Berk, J.M.; Hochstrasser, M.; Brown, A.J. Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation. J. Biol. Chem. 2019, 294, 2436–2448. [Google Scholar] [CrossRef] [PubMed]
- Luo, H.; Jiao, Q.; Shen, C.; Shao, C.; Xie, J.; Chen, Y.; Feng, X.; Zhang, X. Unraveling the roles of endoplasmic reticulum-associated degradation in metabolic disorders. Front. Endocrinol. 2023, 14, 1123769. [Google Scholar] [CrossRef] [PubMed]
- Coates, H.W.; Capell-Hattam, I.M.; Brown, A.J. The mammalian cholesterol synthesis enzyme squalene monooxygenase is proteasomally truncated to a constitutively active form. J. Biol. Chem. 2021, 296, 100731. [Google Scholar] [CrossRef] [PubMed]
- Christianson, J.C.; Jarosch, E.; Sommer, T. Mechanisms of substrate processing during ER-associated protein degradation. Nat. Rev. Mol. Cell Biol. 2023, 24, 777–796. [Google Scholar] [CrossRef] [PubMed]
- Krshnan, L.; van de Weijer, M.L.; Carvalho, P. Endoplasmic reticulum-associated protein degradation. Cold Spring Harb. Perspect. Biol. 2022, 14, a41247. [Google Scholar] [CrossRef] [PubMed]
- Lange, S.M.; Armstrong, L.A.; Kulathu, Y. Deubiquitinases: From mechanisms to their inhibition by small molecules. Mol. Cell 2022, 82, 15–29. [Google Scholar] [CrossRef] [PubMed]
- McClellan, A.J.; Laugesen, S.H.; Ellgaard, L. Cellular functions and molecular mechanisms of non-lysine ubiquitination. Open Biol. 2019, 9, 190147. [Google Scholar] [CrossRef] [PubMed]
- Kelsall, I.R. Non-lysine ubiquitylation: Doing things differently. Front. Mol. Biosci. 2022, 9, 1008175. [Google Scholar] [CrossRef] [PubMed]
- Lei, G.; Zhuang, L.; Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 2022, 22, 381–396. [Google Scholar] [CrossRef] [PubMed]
- Stockwell, B.R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022, 185, 2401–2421. [Google Scholar] [CrossRef]
- Pope, L.E.; Dixon, S.J. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023, 33, 1077–1087. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.W.; Lee, J.-Y.; Oh, M.; Lee, E.-W. An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis. Exp. Mol. Med. 2023, 55, 1620–1631. [Google Scholar] [CrossRef] [PubMed]
- Hong, X.; Roh, W.; Sullivan, R.J.; Wong, K.H.K.; Wittner, B.S.; Guo, H.; Dubash, T.D.; Sade-Feldman, M.; Wesley, B.; Horwitz, E.; et al. The lipogenic regulator SREBP2 induces transferrin in circulating melanoma cells and suppresses ferroptosis. Cancer Discov. 2021, 11, 678–695. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Chakraborty, B.; Safi, R.; Kazmin, D.; Chang, C.-Y.; McDonnell, D.P. Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nat. Commun. 2021, 12, 5103. [Google Scholar] [CrossRef]
- Tang, W.; Xu, F.; Zhao, M.; Zhang, S. Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer. BMC Cancer 2021, 21, 1160. [Google Scholar] [CrossRef]
- Wang, Y.; Shao, W.; Feng, Y.; Tang, J.; Wang, Q.; Zhang, D.; Huang, H.; Jiang, M. Prognostic value and potential biological functions of ferroptosis-related gene signature in bladder cancer. Oncol. Lett. 2022, 24, 301. [Google Scholar] [CrossRef] [PubMed]
- Xu, F.; Zhang, Z.; Zhao, Y.; Zhou, Y.; Pei, H.; Bai, L. Bioinformatic mining and validation of the effects of ferroptosis regulators on the prognosis and progression of pancreatic adenocarcinoma. Gene 2021, 795, 145804. [Google Scholar] [CrossRef] [PubMed]
- Hanahan, D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022, 12, 31–46. [Google Scholar] [CrossRef] [PubMed]
- Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788. [CrossRef] [PubMed]
- Pavlova, N.N.; Zhu, J.; Thompson, C.B. The hallmarks of cancer metabolism: Still emerging. Cell Metab. 2022, 34, 355–377. [Google Scholar] [CrossRef] [PubMed]
- Riscal, R.; Skuli, N.; Simon, M.C. Even cancer cells watch their cholesterol! Mol. Cell 2019, 76, 220–231. [Google Scholar] [CrossRef] [PubMed]
- Qin, W.-H.; Yang, Z.-S.; Li, M.; Chen, Y.; Zhao, X.-F.; Qin, Y.-Y.; Song, J.-Q.; Wang, B.-B.; Yuan, B.; Cui, X.-L.; et al. High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice. Gastroenterology 2020, 158, 1713–1727. [Google Scholar] [CrossRef] [PubMed]
- Xia, W.; Wang, H.; Zhou, X.; Wang, Y.; Xue, L.; Cao, B.; Song, J. The role of cholesterol metabolism in tumor therapy, from bench to bed. Front. Pharmacol. 2023, 14, 928821. [Google Scholar] [CrossRef] [PubMed]
- Ivan, M.; Fishel, M.L.; Tudoran, O.M.; Pollok, K.E.; Wu, X.; Smith, P.J. Hypoxia signaling: Challenges and opportunities for cancer therapy. Semin. Cancer Biol. 2022, 85, 185–195. [Google Scholar] [CrossRef] [PubMed]
- Brown, D.N.; Caffa, I.; Cirmena, G.; Piras, D.; Garuti, A.; Gallo, M.; Alberti, S.; Nencioni, A.; Ballestrero, A.; Zoppoli, G. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer. Sci. Rep. 2016, 6, 19435. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Sun, W.; Zhang, K.; Zheng, H.; Ma, Y.; Lin, D.; Zhang, X.; Feng, L.; Lei, W.; Zhang, Z.; et al. Identification of genes differentially expressed in human primary lung squamous cell carcinoma. Lung Cancer 2007, 56, 307–317. [Google Scholar] [CrossRef] [PubMed]
- Helms, M.W.; Kemming, D.; Pospisil, H.; Vogt, U.; Buerger, H.; Korsching, E.; Liedtke, C.; Schlotter, C.M.; Wang, A.; Chan, S.Y.; et al. Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease. Br. J. Cancer 2008, 99, 774–780. [Google Scholar] [CrossRef] [PubMed]
- Chien, M.; Lee, T.; Kao, C.; Yang, S.; Lee, W. Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis. Mol. Carcinog. 2012, 51, 389–399. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.-Y.; Li, H.-M.; Yu, Z.; Yu, X.-Y.; Guo, K. Expression and significance of squalene epoxidase in squamous lung cancerous tissues and pericarcinoma tissues. Thorac. Cancer 2014, 5, 275–280. [Google Scholar] [CrossRef] [PubMed]
- Souchek, J.J.; Baine, M.J.; Lin, C.; Rachagani, S.; Gupta, S.; Kaur, S.; Lester, K.; Zheng, D.; Chen, S.; Smith, L.; et al. Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br. J. Cancer 2014, 111, 1139–1149. [Google Scholar] [CrossRef]
- D’arcy, M.; Fleming, J.; Robinson, W.R.; Kirk, E.L.; Perou, C.M.; Troester, M.A. Race-associated biological differences among Luminal A breast tumors. Breast Cancer Res. Treat. 2015, 152, 437–448. [Google Scholar] [CrossRef] [PubMed]
- Simigdala, N.; Gao, Q.; Pancholi, S.; Roberg-Larsen, H.; Zvelebil, M.; Ribas, R.; Folkerd, E.; Thompson, A.; Bhamra, A.; Dowsett, M.; et al. Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Res. 2016, 18, 58. [Google Scholar] [CrossRef] [PubMed]
- Stäubert, C.; Krakowsky, R.; Bhuiyan, H.; Witek, B.; Lindahl, A.; Broom, O.; Nordström, A. Increased lanosterol turnover: A metabolic burden for daunorubicin-resistant leukemia cells. Med. Oncol. 2016, 33, 6. [Google Scholar] [CrossRef] [PubMed]
- Stopsack, K.H.; Gerke, T.A.; Sinnott, J.A.; Penney, K.L.; Tyekucheva, S.; Sesso, H.D.; Andersson, S.-O.; Andrén, O.; Cerhan, J.R.; Giovannucci, E.L.; et al. Cholesterol metabolism and prostate cancer lethality. Cancer Res. 2016, 76, 4785–4790. [Google Scholar] [CrossRef] [PubMed]
- Stopsack, K.H.; Gerke, T.A.; Andrén, O.; Andersson, S.-O.; Giovannucci, E.L.; Mucci, L.A.; Rider, J.R. Cholesterol uptake and regulation in high-grade and lethal prostate cancers. Carcinogenesis 2017, 38, 806–811. [Google Scholar] [CrossRef] [PubMed]
- Liu, D.; Wong, C.C.; Fu, L.; Chen, H.; Zhao, L.; Li, C.; Zhou, Y.; Zhang, Y.; Xu, W.; Yang, Y.; et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl. Med. 2018, 10, p9840. [Google Scholar] [CrossRef]
- Liang, J.Q.; Teoh, N.; Xu, L.; Pok, S.; Li, X.; Chu, E.S.H.; Chiu, J.; Dong, L.; Arfianti, E.; Haigh, W.G.; et al. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat. Commun. 2018, 9, 4490. [Google Scholar] [CrossRef] [PubMed]
- Ji, J.; Sundquist, J.; Sundquist, K. Use of terbinafine and risk of death in patients with prostate cancer: A population-based cohort study. Int. J. Cancer 2019, 144, 1888–1895. [Google Scholar] [CrossRef] [PubMed]
- Ge, H.; Zhao, Y.; Shi, X.; Tan, Z.; Chi, X.; He, M.; Jiang, G.; Ji, L.; Li, H. Squalene epoxidase promotes the proliferation and metastasis of lung squamous cell carcinoma cells though extracellular signal-regulated kinase signaling. Thorac. Cancer 2019, 10, 428–436. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.H.; Kim, C.N.; Kang, D.W. Squalene epoxidase correlates E-cadherin expression and overall survival in colorectal cancer patients: The impact on prognosis and correlation to clinicopathologic features. J. Clin. Med. 2019, 8, 632. [Google Scholar] [CrossRef] [PubMed]
- Kim, N.I.; Park, M.H.; Kweon, S.-S.; Cho, N.; Lee, J.S. Squalene epoxidase expression is associated with breast tumor progression and with a poor prognosis in breast cancer. Oncol. Lett. 2021, 21, 259. [Google Scholar] [CrossRef] [PubMed]
- Zhang, E.B.; Zhang, X.; Wang, K.; Zhang, F.; Chen, T.W.; Ma, N.; Ni, Q.Z.; Wang, Y.K.; Zheng, Q.W.; Cao, H.J.; et al. Antifungal agent Terbinafine restrains tumor growth in preclinical models of hepatocellular carcinoma via AMPK-mTOR axis. Oncogene 2021, 40, 5302–5313. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Fang, L.; Liu, W. High SQLE expression and gene amplification correlates with poor prognosis in head and neck squamous cell carcinoma. Cancer Manag. Res. 2021, 13, 4709–4723. [Google Scholar] [CrossRef] [PubMed]
- Jun, S.Y.; Brown, A.J.; Chua, N.K.; Yoon, J.-Y.; Lee, J.-J.; Yang, J.O.; Jang, I.; Jeon, S.-J.; Choi, T.-I.; Kim, C.-H.; et al. Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis. Gastroenterology 2021, 160, 1194–1207. [Google Scholar] [CrossRef] [PubMed]
- Hong, Z.; Liu, T.; Wan, L.; Fa, P.; Kumar, P.; Cao, Y.; Prasad, C.B.; Qiu, Z.; Liu, J.; Wang, H.; et al. Targeting squalene epoxidase interrupts homologous recombination via the ER stress response and promotes radiotherapy efficacy. Cancer Res. 2022, 82, 1298–1312. [Google Scholar] [CrossRef] [PubMed]
- Yao, L.; Li, J.; Zhang, X.; Zhou, L.; Hu, K. Downregulated ferroptosis-related gene SQLE facilitates temozolomide chemoresistance, and invasion and affects immune regulation in glioblastoma. CNS Neurosci. Ther. 2022, 28, 2104–2115. [Google Scholar] [CrossRef]
- Zhao, F.; Huang, Y.; Zhang, Y.; Li, X.; Chen, K.; Long, Y.; Li, F.; Ma, X. SQLE inhibition suppresses the development of pancreatic ductal adenocarcinoma and enhances its sensitivity to chemotherapeutic agents in vitro. Mol. Biol. Rep. 2022, 49, 6613–6621. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Yang, T.; Wang, Q.; Li, Y.; Wu, H.; Zhang, M.; Qi, H.; Zhang, H.; Li, J. Upregulation of SQLE contributes to poor survival in head and neck squamous cell carcinoma. Int. J. Biol. Sci. 2022, 18, 3576–3591. [Google Scholar] [CrossRef] [PubMed]
- You, W.; Ke, J.; Chen, Y.; Cai, Z.; Huang, Z.-P.; Hu, P.; Wu, X. SQLE, a key enzyme in cholesterol metabolism, correlates with tumor immune infiltration and immunotherapy outcome of pancreatic adenocarcinoma. Front. Immunol. 2022, 13, 864244. [Google Scholar] [CrossRef] [PubMed]
- Hu, L.-P.; Huang, W.; Wang, X.; Xu, C.; Qin, W.-T.; Li, D.; Tian, G.; Li, Q.; Zhou, Y.; Chen, S.; et al. Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression. Mol. Ther. 2022, 30, 3284–3299. [Google Scholar] [CrossRef] [PubMed]
- Luo, Z.-W.; Sun, Y.-Y.; Xia, W.; Xu, J.-Y.; Xie, D.-J.; Jiao, C.-M.; Dong, J.-Z.; Chen, H.; Wan, R.-W.; Chen, S.-Y.; et al. Physical exercise reverses immuno-cold tumor microenvironment via inhibiting SQLE in non-small cell lung cancer. Mil. Med. Res. 2023, 10, 39. [Google Scholar] [CrossRef] [PubMed]
- Xu, R.; Song, J.; Ruze, R.; Chen, Y.; Yin, X.; Wang, C.; Zhao, Y. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. Cell Death Dis. 2023, 14, 497. [Google Scholar] [CrossRef] [PubMed]
- Zhao, X.; Guo, B.; Sun, W.; Yu, J.; Cui, L. Targeting squalene epoxidase confers metabolic vulnerability and overcomes chemoresistance in HNSCC. Adv. Sci. 2023, 10, e2206878. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Wu, W.; Jiao, H.; Chen, Y.; Ji, X.; Cao, J.; Yin, F.; Yin, W. Squalene epoxidase promotes hepatocellular carcinoma development by activating STRAP transcription and TGF-β/SMAD signalling. Br. J. Pharmacol. 2023, 180, 1562–1581. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Cao, Z.; Song, C.; Wei, Z.; Zhou, M.; Chen, S.; Ran, J.; Zhang, H.; Zou, H.; Han, S.; et al. Cholesterol metabolism modulation nanoplatform improves photo-immunotherapeutic effect in oral squamous cell carcinoma. Adv. Healthc. Mater. 2023, 12, e2300018. [Google Scholar] [CrossRef] [PubMed]
- Xie, Y.; Jiang, Y.; Wu, Y.; Su, X.; Zhu, D.; Gao, P.; Yuan, H.; Xiang, Y.; Wang, J.; Zhao, Q.; et al. Association of serum lipids and abnormal lipid score with cancer risk: A population-based prospective study. J. Endocrinol. Investig. 2023, 47, 367–376. [Google Scholar] [CrossRef]
- Yuan, F.; Wen, W.; Jia, G.; Long, J.; Shu, X.-O.; Zheng, W. Serum Lipid Profiles and Cholesterol-Lowering Medication Use in Relation to Subsequent Risk of Colorectal Cancer in the UK Biobank Cohort. Cancer Epidemiol. Biomark. Prev. 2023, 32, 524–530. [Google Scholar] [CrossRef] [PubMed]
- Xie, J.; Nguyen, C.M.; Turk, A.; Nan, H.; Imperiale, T.F.; House, M.; Huang, K.; Su, J. Aberrant cholesterol metabolism in colorectal cancer represents a targetable vulnerability. Genes Dis. 2023, 10, 1172–1174. [Google Scholar] [CrossRef] [PubMed]
- Lin, J.; Song, T.; Li, C.; Mao, W. GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer. Biochim. Biophys. Acta Mol. Cell Res. 2020, 1867, 118659. [Google Scholar] [CrossRef] [PubMed]
- Hassin, O.; Oren, M. Drugging p53 in cancer: One protein, many targets. Nat. Rev. Drug Discov. 2023, 22, 127–144. [Google Scholar] [CrossRef]
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Talamantes, S.; Lisjak, M.; Gilglioni, E.H.; Llamoza-Torres, C.J.; Ramos-Molina, B.; Gurzov, E.N. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Rep. 2023, 5, 100811. [Google Scholar] [CrossRef] [PubMed]
- Rinella, M.E.; Neuschwander-Tetri, B.A.; Siddiqui, M.S.; Abdelmalek, M.F.; Caldwell, S.; Barb, D.; Kleiner, D.E.; Loomba, R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023, 77, 1797–1835. [Google Scholar] [CrossRef] [PubMed]
- Huang, D.Q.; Singal, A.G.; Kono, Y.; Tan, D.J.; El-Serag, H.B.; Loomba, R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022, 34, 969–977. [Google Scholar] [CrossRef] [PubMed]
- Sanyal, A.J.; Harrison, S.A.; Ratziu, V.; Abdelmalek, M.F.; Diehl, A.M.; Caldwell, S.; Shiffman, M.L.; Schall, R.A.; Jia, C.; McColgan, B.; et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: Data from the Simtuzumab trials. Hepatology 2019, 70, 1913–1927. [Google Scholar] [CrossRef] [PubMed]
- Fujiwara, N.; Nakagawa, H. Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease. Cancer Sci. 2023, 114, 3825–3833. [Google Scholar] [CrossRef] [PubMed]
- Huang, D.Q.; Singal, A.G.; Kanwal, F.; Lampertico, P.; Buti, M.; Sirlin, C.B.; Nguyen, M.H.; Loomba, R. Hepatocellular carcinoma surveillance—Utilization, barriers and the impact of changing aetiology. Nat. Rev. Gastroenterol. Hepatol. 2023, 20, 797–809. [Google Scholar] [CrossRef] [PubMed]
- Li, Q.; Li, Z.; Luo, T.; Shi, H. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. Mol. Biomed. 2022, 3, 47. [Google Scholar] [CrossRef] [PubMed]
- Ali, S.; Rehman, M.U.; Yatoo, A.M.; Arafah, A.; Khan, A.; Rashid, S.; Majid, S.; Ali, A.; Ali, M.N. TGF-beta signaling pathway: Therapeutic targeting and potential for anti-cancer immunity. Eur. J. Pharmacol. 2023, 947, 175678. [Google Scholar] [CrossRef] [PubMed]
- Leong, A.Z.-X.; Lee, P.Y.; Mohtar, M.A.; Syafruddin, S.E.; Pung, Y.-F.; Low, T.Y. Short open reading frames (sORFs) and microproteins: An update on their identification and validation measures. J. Biomed. Sci. 2022, 29, 19. [Google Scholar] [CrossRef] [PubMed]
- Sella, T.; Weiss, A.; Mittendorf, E.A.; King, T.A.; Pilewskie, M.; Giuliano, A.E.; Metzger-Filho, O. Neoadjuvant endocrine therapy in clinical practice: A review. JAMA Oncol. 2021, 7, 1700–1708. [Google Scholar] [CrossRef]
- Parada, H.; Sun, X.; Fleming, J.M.; Williams-DeVane, C.R.; Kirk, E.L.; Olsson, L.T.; Perou, C.M.; Olshan, A.F.; Troester, M.A. Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study. Breast Cancer Res. 2017, 19, 131. [Google Scholar] [CrossRef] [PubMed]
- Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers 2020, 6, 92. [Google Scholar] [CrossRef] [PubMed]
- Gebrael, G.; Fortuna, G.G.; Sayegh, N.; Swami, U.; Agarwal, N. Advances in the treatment of metastatic prostate cancer. Trends Cancer 2023, 9, 840–854. [Google Scholar] [CrossRef] [PubMed]
- Cai, M.; Song, X.-L.; Li, X.-A.; Chen, M.; Guo, J.; Yang, D.-H.; Chen, Z.; Zhao, S.-C. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resist. Updates 2023, 68, 100962. [Google Scholar] [CrossRef] [PubMed]
- Li, B.; Qin, Y.; Yu, X.; Xu, X.; Yu, W. Lipid raft involvement in signal transduction in cancer cell survival, cell death and metastasis. Cell Prolif. 2022, 55, e13167. [Google Scholar] [CrossRef] [PubMed]
- Mizrahi, J.D.; Surana, R.; Valle, J.W.; Shroff, R.T. Pancreatic cancer. Lancet 2020, 395, 2008–2020. [Google Scholar] [CrossRef]
- Berger, T.R.; Wen, P.Y.; Lang-Orsini, M.; Chukwueke, U.N. World Health Organization 2021 classification of central nervous system tumors and implications for therapy for adult-type gliomas: A review. JAMA Oncol. 2022, 8, 1493–1501. [Google Scholar] [CrossRef] [PubMed]
- Mahoney, C.E.; Pirman, D.; Chubukov, V.; Sleger, T.; Hayes, S.; Fan, Z.P.; Allen, E.L.; Chen, Y.; Huang, L.; Liu, M.; et al. A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition. Nat. Commun. 2019, 10, 96. [Google Scholar] [CrossRef] [PubMed]
- Liu, C.; Chen, H.; Hu, B.; Shi, J.; Chen, Y.; Huang, K. New insights into the therapeutic potentials of statins in cancer. Front. Pharmacol. 2023, 14, 1188926. [Google Scholar] [CrossRef] [PubMed]
- Mei, Z.; Liang, M.; Li, L.; Zhang, Y.; Wang, Q.; Yang, W. Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int. J. Cancer 2017, 140, 1068–1081. [Google Scholar] [CrossRef] [PubMed]
- Islam, M.M.; Poly, T.N.; Walther, B.A.; Yang, H.C.; Li, Y.C. Statin use and the risk of hepatocellular carcinoma: A meta-analysis of observational studies. Cancers 2020, 12, 671. [Google Scholar] [CrossRef] [PubMed]
- Cheung, K.S.; Yeung, Y.W.M.; Wong, W.S.; Li, B.; Seto, W.K.; Leung, W.K. Statins associate with lower risk of biliary tract cancers: A systematic review and meta-analysis. Cancer Med. 2023, 12, 557–568. [Google Scholar] [CrossRef]
- Nagaraja, R.; Olaharski, A.; Narayanaswamy, R.; Mahoney, C.; Pirman, D.; Gross, S.; Roddy, T.P.; Popovici-Muller, J.; Smolen, G.A.; Silverman, L. Preclinical toxicology profile of squalene epoxidase inhibitors. Toxicol. Appl. Pharmacol. 2020, 401, 115103. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Dong, J.; Yu, Z. Pleiotropic use of Statins as non-lipid-lowering drugs. Int. J. Biol. Sci. 2020, 16, 2704–2711. [Google Scholar] [CrossRef] [PubMed]
- Ward, N.C.; Watts, G.F.; Eckel, R.H. Statin toxicity. Circ. Res. 2019, 124, 328–350. [Google Scholar] [CrossRef]
- Chen, W.; Xu, J.; Wu, Y.; Liang, B.; Yan, M.; Sun, C.; Wang, D.; Hu, X.; Liu, L.; Hu, W.; et al. The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis. Int. J. Biol. Sci. 2023, 19, 2879–2896. [Google Scholar] [CrossRef]
- Horie, M.; Tsuchiya, Y.; Hayashi, M.; Iida, Y.; Iwasawa, Y.; Nagata, Y.; Sawasaki, Y.; Fukuzumi, H.; Kitani, K.; Kamei, T. NB-598: A potent competitive inhibitor of squalene epoxidase. J. Biol. Chem. 1990, 265, 18075–18078. [Google Scholar] [CrossRef] [PubMed]
- Sawada, M.; Washizuka, K.-I.; Okumura, H. Synthesis and biological activity of a novel squalene epoxidase inhibitor, FR194738. Bioorganic Med. Chem. Lett. 2004, 14, 633–637. [Google Scholar] [CrossRef] [PubMed]
- ClinicalTrials.gov. Search Results for “Cancer” and “FR194738”. 2023. Available online: https://clinicaltrials.gov/search?cond=cancer&intr=FR194738 (accessed on 12 September 2023).
- ClinicalTrials.gov. Search Results for “Cancer” and “NB598”. 2023. Available online: https://clinicaltrials.gov/search?cond=cancer&intr=NB598 (accessed on 12 September 2023).
- ClinicalTrials.gov. Search Results for “Cancer” and “Terbinafine”. 2023. Available online: https://clinicaltrials.gov/search?cond=cancer&intr=Terbinafine (accessed on 12 September 2023).
- ClinicalTrials.gov. Search Results for “Cancer” and “Cmpd-4”. 2023. Available online: https://clinicaltrials.gov/search?cond=cancer&intr=Cmpd-4 (accessed on 12 September 2023).
- Rozman, D.; Monostory, K. Perspectives of the non-statin hypolipidemic agents. Pharmacol. Ther. 2010, 127, 19–40. [Google Scholar] [CrossRef] [PubMed]
- Belter, A.; Skupinska, M.; Giel-Pietraszuk, M.; Grabarkiewicz, T.; Rychlewski, L.; Barciszewski, J. Squalene monooxygenase—A target for hypercholesterolemic therapy. Biol. Chem. 2011, 392, 1053–1075. [Google Scholar] [CrossRef]
- Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019, 18, 41–58. [Google Scholar] [CrossRef] [PubMed]
- Schipper, L.J.; Zeverijn, L.J.; Garnett, M.J.; Voest, E.E. Can drug repurposing accelerate precision oncology? Cancer Discov. 2022, 12, 1634–1641. [Google Scholar] [CrossRef] [PubMed]
- Foretz, M.; Guigas, B.; Viollet, B. Metformin: Update on mechanisms of action and repurposing potential. Nat. Rev. Endocrinol. 2023, 19, 460–476. [Google Scholar] [CrossRef] [PubMed]
- Nuvola, G.; Santoni, M.; Rizzo, M.; Rosellini, M.; Mollica, V.; Rizzo, A.; Marchetti, A.; Battelli, N.; Massari, F. Adapting to hormone-therapy resistance for adopting the right therapeutic strategy in advanced prostate cancer. Expert Rev. Anticancer Ther. 2023, 23, 593–600. [Google Scholar] [CrossRef]
- Lu, S.S.M.; Mohammed, Z.; Häggström, C.; Myte, R.; Lindquist, E.; Gylfe, Å.; Van Guelpen, B.; Harlid, S. Antibiotics use and subsequent risk of colorectal cancer: A Swedish nationwide population-based study. J. Natl. Cancer Inst. 2022, 114, 38–46. [Google Scholar] [CrossRef] [PubMed]
Regulation Level | Involved Molecule | Mechanism | References |
---|---|---|---|
End product | Cholesterol | Cholesterol-accelerated degradation is dependent on the SQLE N100 regulatory domain of SQLE and happens at the post-transcriptional level. | [18,20] |
End product | Cholesterol | The interaction between cholesterol and SQLE was confirmed using a chemoproteomic strategy. | [29] |
End product | Cholesterol enantiomer | Ent-cholesterol also accelerates the proteasomal degradation of SQLE via suppression of the activation of SREBP2. | [33] |
Substrate | Squalene | Squalene directly binds to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. | [34] |
Other | Unsaturated fatty acids | SQLE is stabilized by unsaturated fatty acids. | [35] |
Other | – | Hypoxia-induced squalene accumulation promotes partial degradation of SQLE through MARCH6 to a constitutively active truncated form. | [36] |
Transcription | SREBP2 | When cholesterol levels are low, SREBP2 enters the nucleus to bind to the SRE sequence in the promoters of target genes and induce the expression of them. | [1,3,37] |
Transcription | NF-Y | NF-Y sites were identified on an SQLE promoter and act as cofactors for transcription. | [16,38] |
Transcription | Sp1 | Sp1 sites were identified on an SQLE promoter and act as cofactors for transcription. | [38,39] |
Transcription | YY1 | A putative binding site for YY1 was predicted on an SQLE promoter. | [16] |
Post-transcription | MARCH6 | MARCH6 acts as an E3 ligase, and its overexpression reduces SQLE abundance in a RING-dependent manner. | [40] |
Post-transcription | UBE2J2 | UBE2J2 was identified as the primary E2 ubiquitin-conjugating enzyme essential for MARCH6-dependent degradation of SQLE in mammalian cells. | [41] |
Post-transcription | VCP | VCP regulates SQLE N100 in a MARCH6-dependent manner. | [42] |
Post-transcription | Serine residues for ubiquitination | Four serines (Ser-59, Ser-61, Ser-83, Ser-87) are critical for cholesterol-accelerated degradation, with Ser-83 used as a ubiquitination site. | [43] |
Transcription | MiR-133b | SQLE is a direct target of miR-133b in esophageal cancer. | [44] |
Post-transcription | CASIMO1 | CASIMO1 interacts with SQLE and modulates lipid droplet accumulation in breast cancer. | [45] |
Transcription | Lnc030, PCBP2 | Lnc030 cooperates with PCBP2 to stabilize SQLE mRNA in breast cancer. | [46] |
Transcription | MiR-205 | MiR-205 controls SQLE expression through the 3′-UTR of SQLE mRNA in prostate cancer. | [47] |
Transcription | EZH2 | EZH2 inhibitor promotes SQLE expression by reducing H3K27me3 modification. | [48] |
Transcription | P53 | P53 directly represses the expression of SQLE in an SREBP2-independent manner. | [49] |
Transcription | PTEN/p53 | PTEN/p53 deficiency enhances SQLE expression via the activation of SREBP2. | [50] |
Transcription | NR4A2 | NR4A2 binds to the promoter region of SQLE to activate it in microglia. | [51] |
Agent Types | Agent Name | Description |
---|---|---|
Ferroptosis prerequisites | PUFA-PLs | ACSL4, LPCAT3, and ACC are enzymes responsible for the synthesis and peroxidation of PUFA-PLs. |
Iron | Iron is involved in the Fenton reaction for the direct peroxidation of PUFA-PLs; it also acts as a cofactor for enzymes that participate in lipid peroxidation (such as ALOX and POR). | |
Mitochondrial metabolism | Mitochondrial ROS are critical for lipid peroxidation and ferroptosis onset; electron transport and proton pumping in mitochondria are important for ATP production; and the role of mitochondria in biosynthetic pathways in cellular metabolism contributes to ferroptosis. | |
Ferroptosis defence mechanisms | SLC7A11–GSH–GPX4 system | This is the major cellular defence system for ferroptosis. |
FSP1–CoQH2 system | FSP1 is capable of reducing CoQ to CoQH2. | |
DHODH–CoQH2 system | DHODH can reduce CoQ to CoQH2. | |
GCH1–BH4 system | GCH1 suppresses ferroptosis through the generation of BH4 as a radical-trapping antioxidant and mediates the production of CoQH2 and PLs containing two PUFA tails. |
Year | Tumor Type | Study Type | Prognostic Significance | Involved Pathways/Mechanisms | References |
---|---|---|---|---|---|
2007 | NSCLC | 2 | – | SQLE mRNA was higher in tumor samples compared to normal lung samples. | [95] |
2008 | BRCA | 2 | DFS in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA. | – | [96] |
2012 | OSCC | 1 | – | Terbinafine decreased cell viability, inhibited DNA synthesis, and induced G0/G1 cell cycle arrest. | [97] |
2014 | NSCLC | 2 | SQLE mRNA levels were negatively associated with OS. | SQLE mRNA and protein in LUSC were significantly elevated. | [98] |
2014 | PC | 1, 2 | – | 11 genes including SQLE were consistently associated with radioresistance in the studied cell lines. | [99] |
2015 | BRCA | 2 | High SQLE was associated with higher mortality among luminal A BRCA. | SQLE mRNA was differentially expressed by race among luminal A breast cancers and associated with survival. | [100] |
2016 | BRCA | 1, 2 | SQLE overexpression was associated with worse OS. | SQLE was identified as a bona fide metabolic oncogene by amplification. | [94] |
2016 | BRCA | 1 | – | In primary ER+ BRCA, increased expression of SQLE were significantly associated with a poor response to endocrine therapy. | [101] |
2016 | LK | 1 | – | The cholesterol biosynthetic pathway was upregulated in daunorubicin-resistant leukemia cells. | [102] |
2016 | PrC | 3 | – | Men with high SQLE expression were more likely to have lethal cancer and tumor angiogenesis. | [103] |
2017 | EC | 1, 2 | – | SQLE is a downstream target gene of miR-133b and induces EMT. | [44] |
2017 | PrC | 2, 3 | – | PrC patients that progressed to lethal disease relied on de novo cholesterol synthesis via SQLE. | [104] |
2018 April | HCC | 1, 2 | High SQLE expression was an independent prognostic factor associated with poor DFS. | SQLE silenced PTEN via induction of the ROS–DNMT3A axis and activated the PTEN/PI3K/AKT/mTOR pathway. | [105] |
2018 August | BRCA | 1, 2 | – | Knockdown of CASIMO1 decreased SQLE protein, lipid droplets, and ERK phosphorylation. | [45] |
2018 October | HCC | 1, 2 | – | SQLE was upregulated in both NASH and steatosis HCCs. | [106] |
2019 April | PrC | 2 | – | Terbinafine decreased the risk of death from PrC and risk of death overall. | [107] |
2019 March | NSCLC | 1, 2 | Higher SQLE indicated shorter OS in LUSC. | SQLE could interact with ERK to enhance its phosphorylation. | [108] |
2019 May | CRC | 2 | SQLE-positive patients had shorter RFS and poorer OS than SQLE-negative ones. | – | [109] |
2020 November | BRCA | 1, 2 | – | Lnc030 cooperates with PCBP2 to stabilize SQLE mRNA and activates PI3K/Akt signaling to govern breast CSC stemness. | [46] |
2021 April | BRCA | 2 | High SQLE expression was associated with poor DFS and OS. | – | [110] |
2021 August | CRC | 1, 2 | CRC patients with higher SQLE expression had shorter OS. | Inhibition of SQLE reduced calcitriol and CYP24A1, increased intracellular Ca2+, and suppressed MAPK signaling. | [11] |
2021 August | HCC | 1 | – | Terbinafine and sorafenib inhibit mTORC1 signaling via AMPK activation and induce double-stranded DNA breaks. | [111] |
2021 August | PC | 1, 2 | – | Blocking PTGS2 and SQLE suppressed the protein expression of cyclin D1 and N-cadherin and facilitated E-cadherin. | [86] |
2021 August | PrC | 1, 2 | High SQLE is significantly associated with shorter biochemical RFS and worse RFS and OS. | SQLE expression is controlled by micro-RNA 205. | [47] |
2021 June | HNSCC | 1, 2 | High SQLE expression was significantly associated with poor OS and PFS. | High SQLE expression promoted cell proliferation and was associated with the T stage in HNSCC patients. | [112] |
2021 March | CRC | 1, 2 | The median survival of CRC patients with high SQLE mRNA levels was 80% higher than those with low SQLE levels. | SQLE reduction inhibited GSK-3β and p53 degradation, inducing EMT to aggravate CRC progression. | [113] |
2021 May | HNSCC | 1, 2 | HCC patients with higher SQLE expression had poorer OS, RFS, PFS, and disease-specific survival. | Inhibition of the histone methyltransferase EZH2 strongly induced the expression of the SQLE gene. | [48] |
2021 October | HCC | 1, 2 | – | P53 directly represses the expression of SQLE in an SREBP2-independent manner. | [49] |
2022 April | BRCA | 1, 2 | Patients with high SQLE had worse OS and DFS. | SQLE inhibition resulted in squalene accumulation and triggered ER stress, which activated the WIP1–ATM axis. | [114] |
2022 April | NSCLC | 1, 2 | SQLE was identified as a predictor of poor OS. | Inhibition of SQLE led to the accumulation of squalene, inducing ER stress and activating the WIP1–ATM axis. | [114] |
2022 December | GBM | 1, 2 | Low SQLE expression was significantly associated with poor OS. | SQLE suppressed ERK-mediated TMZ chemoresistance and metastasis of GBM cells. | [115] |
2022 July | PC | 1, 2 | PDAC patients with higher SQLE expression had shorter OS. | SQLE silencing blocked the cell cycle in the S phase. | [116] |
2022 May | HNSCC | 1, 2 | The OS and PFS of patients with high SQLE expression were notably shorter. | SQLE overexpression mediated HNSCC progression through PI3K/Akt signaling. | [117] |
2022 May | PC | 1, 2 | SQLE predicted poor DFS and OS. | SQLE was significantly associated with tumor immune cell infiltration and immune checkpoint expression. | [118] |
2022 November | CRC | 1, 2 | High SQLE mRNA levels were associated with poor OS in patients with CRC. | SQLE induced cell cycle progression, gut dysbiosis, and increased secondary bile acids and suppressed apoptosis. | [12] |
2022 October | CRC | 1 | – | Terbinafine led to nucleotide synthesis disruption, deoxyribonucleotide starvation, and cell cycle arrest. | [119] |
2022 September | PrC | 1, 2 | SQLE expression levels were positively correlated with worse OS in patients with CRPC. | PTEN/p53 deficiency transcriptionally upregulated SQLE via activation of SREBP2 and inhibited the PI3K/Akt/GSK3β pathway. | [50] |
2023 April | GBM | 1, 2 | – | NR4A2 activated SQLE to dysregulate cholesterol homeostasis in microglia. | [51] |
2023 August | NSCLC | 1, 2 | – | Physical exercise could significantly inhibit SQLE expression and reverse the immuno-cold TIME. | [120] |
2023 August | PC | 1,2 | Patients with higher SQLE expression levels had worse OS and DFS. | SQLE inhibition led to ER stress and apoptosis; SQLE activated the Src/PI3K/Akt signaling pathway. | [121] |
2023 July | HNSCC | 1, 2 | High SQLE expression was correlated with shorter OS/DFS time. | SQLE inactivation suppressed the global c-Myc transcriptional program in CSCs. | [122] |
2023 June | HCC | 1, 2 | – | SQLE promoted tumor growth via TGF-β/SMAD signaling, which is critically dependent on STRAP. | [123] |
2023 September | OSCC | 1, 2 | Higher levels of SQLE expression were associated with shorter OS. | SQLE induced the transformation of CD4+ T cells to Treg cells and promoted tumor development. | [124] |
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Zhang, L.; Cao, Z.; Hong, Y.; He, H.; Chen, L.; Yu, Z.; Gao, Y. Squalene Epoxidase: Its Regulations and Links with Cancers. Int. J. Mol. Sci. 2024, 25, 3874. https://doi.org/10.3390/ijms25073874
Zhang L, Cao Z, Hong Y, He H, Chen L, Yu Z, Gao Y. Squalene Epoxidase: Its Regulations and Links with Cancers. International Journal of Molecular Sciences. 2024; 25(7):3874. https://doi.org/10.3390/ijms25073874
Chicago/Turabian StyleZhang, Lin, Zheng Cao, Yuheng Hong, Haihua He, Leifeng Chen, Zhentao Yu, and Yibo Gao. 2024. "Squalene Epoxidase: Its Regulations and Links with Cancers" International Journal of Molecular Sciences 25, no. 7: 3874. https://doi.org/10.3390/ijms25073874