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
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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
APA StyleZhang, L., Cao, Z., Hong, Y., He, H., Chen, L., Yu, Z., & Gao, Y. (2024). Squalene Epoxidase: Its Regulations and Links with Cancers. International Journal of Molecular Sciences, 25(7), 3874. https://doi.org/10.3390/ijms25073874