Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53
Abstract
:1. Introduction: The Significance of Autophagy in Tumor Cells
2. Molecular Control of Autophagy
3. Histone Deacetylases
4. Histone Deacetylase Inhibitors
5. Mechanisms of Histone Deacetylase Inhibitor-Induced Cell Death
6. HDACi-Induced Cell Death via the Non-Histone Protein p53
7. The HDAC Inhibitor SAHA
8. Mechanisms of HDAC-Induced Autophagic Cell Death
9. Mechanisms of HDACi-Induced Autophagic Cell Death
10. HDACi-Induced Regulatory Pathways of Autophagy
11. Autophagic Cell Death and Its Regulation by p53
12. Conclusions and Future Directions
Acknowledgments
Conflicts of Interest
References
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Target HDAC | Molecular Mechanism | HDACi | Cell Type | Autophagy Monitoring | Ref. |
---|---|---|---|---|---|
HDAC1 | FK228; HDAC1 siRNA | HeLa | LC3-I/-II WB; MDC staining; Lysotracker | [184] | |
HDAC1/HDAC2 | Phenylephrine-triggered autophagy | TSA; ATG5/BECN1 RNAi | Cardio- myocytes | LC3-I/-II WB; GFP-LC3 | [185] |
HDAC6 * | autophagosome-lysosome fusion control; targets aggresomes and damaged mitochondria | Tubacin; HDAC6 siRNA | MEF | LC3-I/-II, p62 WB; mCherry GFP-LC3; ATG5 KO | [186,187] |
HDAC7 | Reduced ERK activation | HDAC7 siRNA | MEC | LC3-I/-II, p62 WB; AVO | [188] |
HDAC10 | Acetylation of HSP70 | Bufexamac, tubastatin | LC3-I/-II, Beclin-1 WB; AVO; TEM | [189] | |
Sirt1 | Forms complex with Atg5, Atg7, and ATG8 | Sirt1 KO | MEF | LC3-I/-II; GFP-LC3 | [190] |
Sirt2 | Cytosolic FoxO1 acetylation; ATG7 activation | FoxO1 RNAi | HCT116, HeLa | LC3-I/-II, p62 ATG5-12 WB; GFP-LC3; ATG5 KO | [191] |
SIRT6 | Activation by oxidative stress; mTOR inhibition | Sirt6 siRNA | SH-SY5Y, PC12 | LC3-I/-II WB; GFP-LC3 | [192] |
SIRT6 | Attenuation of IGF-Akt-mTOR signaling | SIRT6 siRNA | HBECs | p62, LC3-I/-II WB; GFP-LC3 | [193] |
Molecular Mechanism | Additional Mechanism | HDACi | Cell Type | Autophagy Monitoring | Ref. |
---|---|---|---|---|---|
mTOR Inhibition | S6rp phosphorylation; increased p21 expression | SAHA | ESS-1 | GFP-LC3; MDC staining; TEM | [120,171] |
Increase of LC3 expression; activation of ULK-1 complex | SAHA | MEFs, T98G Glioblastoma | p62, LC3-I/-II, ATG3, ATG7 WB; GFP-LC3 | [173] | |
Beclin-1 upregulation | SAHA, Butyrate | HelaS3 | GFP-LC3; AVO; FACS | [170,177] | |
Induction of ER stress response | SAHA, OSU-HDAC42 | HCC, Hep3B, HepG2 | LC3-I/-II WB; GFP-LC3; TEM | [178] | |
ROS accumulation via Cat D, repression of TRX; BECN1 and ATG-7 upregulation. | SAHA | Jurkat T-leukemia | BECN1, Atg5, 7, 12 LC3-I/-II WB; GFP-LC3; AVO; TEM | [180] | |
BECN1 protein upregulation. and p62 downregulation | SAHA | Gliobastoma stem cells | LC3-I/-II, BECN1, p62 WB; AVO; IF, TEM | [181] | |
* CASP and CPN-1 activation; reduced ATG expression | MGCD0103 | Primary CLL | p62, LC3-I/-II, ATG5-12; BECN1 WB; | [198] | |
Increased ATG5 expression | Apcidin | Salivary MEC | LC3-I/-II, p62 WB; AVO | [209] | |
ROS Accumulation | CathD upregulation and TRX repression | SAHA | K562, LAMA 84 CMLL | N-acetyl-cysteine, chloroquine | [182] |
Activation of MAPK proteins: ERK1/2 and JNK; LC3 and ATG12 upregulation | FK228 + bortezo-mib | Gastric carcinoma (GC) | LC3-I/-II, Beclin-1, ATG-12 WB | [199] | |
p38 MAPK switch to apoptosis; ERK activation | M-275 | HCT116 | LC3-I/-II ATG5,7 WB; GFP-LC3; TEM | [200] | |
p21 CIP/WAF1 Upregulation | SAHA, H40 | PC-3M, HL-60 | MDC staining | [201] | |
Downregulation of pERK/NF-κB signaling | MRJF4 | PC3 | LC3-I/-II WB; TEM | [202] | |
NF-κB Hyperacetyl-ation | Induction of NF-κB target genes | SAHA, MS-275 | PC3 | Expr. Profiling/ATGs; LC3-I/-II, p62 WB | [206] |
AIF nucleus Translocation | FK228 | MRT | LC3-I/-II; LC3 IF; TEM | [205] | |
Apoptosome Inactivation | Independent of p53; Deletion of Apaf-1/Casp-9 | LAQ824, LBH589 | Eμ-myc lymphomas | LC3-I/-II WB; TEM | [207] |
FoxO1 Transcription | ATG expression; mTOR suppression via SESN3 | SAHA, TSA | HepG2, HCT116 | LC3, p62 WB; GFP-LC3; | [12] |
DAPK Upregulation | LBH589 | HCT116 | p62 WB; LC3-I/-II WB; LC3 IF; AVO | [176] | |
ATG7 Acetylation * | Autophagy interactome acetylation; increased mitochondrial mass and ROS formation | SAHA, TSA, LBH589, JQ2 | Megakaryo-blastic leukemia | GFP-LC3; mCherry-LC3 | [11] |
ATG Gene Upregulation * | Independent of p53 acetylation | Tenovin-6 | CLL | LC3-I/LC3-II, p62 WB; TEM | [208] |
p53 Acetylation | Increased p53-dependent cell cycle arrest and apoptosis | Sirtinol | MCF-7 | LC3-I/-II WB; AVO; MDC staining | [203] |
p53 activation. by reducing MDM2 expression; cell cycle arrest and apodosis | MHY2256 | MCF-7 | LC3-I/-II BECN1 ATG5, 7 WB; AVO | [204] | |
p53-Deficiency | mTOR inhibition | SAHA | ESS-1 | p-mTOR WB; MDC staining, GFP-LC3 | [197] |
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Mrakovcic, M.; Kleinheinz, J.; Fröhlich, L.F. Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53. Int. J. Mol. Sci. 2017, 18, 1883. https://doi.org/10.3390/ijms18091883
Mrakovcic M, Kleinheinz J, Fröhlich LF. Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53. International Journal of Molecular Sciences. 2017; 18(9):1883. https://doi.org/10.3390/ijms18091883
Chicago/Turabian StyleMrakovcic, Maria, Johannes Kleinheinz, and Leopold F. Fröhlich. 2017. "Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53" International Journal of Molecular Sciences 18, no. 9: 1883. https://doi.org/10.3390/ijms18091883