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Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach

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Abstract

Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.

Key Points

1. This review aims to determine the association between the post-translational modulation of autophagy proteins and the regulatory pathways.

2. This review identifies the impact of a variety of autophagic inhibitors and epigenetic drugs on the maintenance and development of the process of autophagy thus revealing the role of these autophagic regulators in cancer therapy.

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Abbreviations

CMA:

Chaperone mediated autophagy

ELP3:

Elongator complex protein 3

GBM:

Glioblastoma multiforme

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

LAMP:

Lysosome-associated membrane protein

MPP:

Mitochondrial Processing Peptidase

mTORC1:

Mammalian target of rapamycin complex 1

NBR1:

Neighbor of BRCA1 gene 1

PAK1:

p21-activated kinase 1

PAS:

Phagophore assembly site

PE:

Phosphatidyl ethanolamine

PTM:

Post-translational modification

SNAP29:

Synaptosome associated protein 29

TFEB:

Transcription factor EB

TOPK:

T-LAK cell‐originated protein kinase

TRAF6:

Tumor necrosis factor receptor-associated factor 6

UVRAG:

UV radiation resistance associated

VAMP8:

Vesicle associated membrane protein 8

ZBTB16:

Zinc finger and BTB domain-containing protein 16

References

  1. Lim SM, Mohamad Hanif EA, Chin SF (2021) Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect. Cell Biosci 11(1):56. https://doi.org/10.1186/s13578-021-00570-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20(3):460–473. https://doi.org/10.1089/ars.2013.5371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chowdhury SG, Bhattacharya D, Karmakar P (2022) Exosomal long noncoding RNAs - the lead thespian behind the regulation, cause and cure of autophagy-related Diseases. Mol Biol Rep 49(7):7013–7024. https://doi.org/10.1007/s11033-022-07514-x

    Article  CAS  PubMed  Google Scholar 

  4. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24(1):24–41. https://doi.org/10.1038/cr.2013.168

    Article  CAS  PubMed  Google Scholar 

  5. Oku M, Sakai Y (2018) Three distinct types of Microautophagy Based on Membrane Dynamics and Molecular Machineries. BioEssays 40(6):e1800008. https://doi.org/10.1002/bies.201800008

    Article  PubMed  Google Scholar 

  6. Bejarano E, Cuervo AM (2010) Chaperone-mediated autophagy. Proc Am Thorac Soc 7(1):29–39. https://doi.org/10.1513/pats.200909-102JS

    Article  PubMed  PubMed Central  Google Scholar 

  7. Guo F, Liu X, Cai H, Le W (2018) Autophagy in neurodegenerative Diseases: pathogenesis and therapy. Brain Pathol 28(1):3–13. https://doi.org/10.1111/bpa.12545

    Article  CAS  PubMed  Google Scholar 

  8. Shu F, Xiao H, Li QN et al (2023) Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther 8(1):32. https://doi.org/10.1038/s41392-022-01300-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yun CW, Lee SH (2018) The roles of Autophagy in Cancer. Int J Mol Sci 19(11):3466. https://doi.org/10.3390/ijms19113466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. George MD, Baba M, Scott SV, Mizushima N et al (2000) Apg5p functions in the sequestration step in the cytoplasm-to-vacuole targeting and macroautophagy pathways. Mol Biol Cell 11(3):969–982. https://doi.org/10.1091/mbc.11.3.969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Orsi A, Razi M, Dooley HC, Robinson D et al (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23(10):1860–1873. https://doi.org/10.1091/mbc.E11-09-0746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takahara T, Amemiya Y, Sugiyama R, Maki M, Shibata H (2020) Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. J Biomed Sci 27(1):87. https://doi.org/10.1186/s12929-020-00679-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noda NN, Fujioka Y (2015) Atg1 family kinases in autophagy initiation. Cell Mol Life Sci 72(16):3083–3096. https://doi.org/10.1007/s00018-015-1917-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park JM, Jung CH, Seo M, Otto NM et al (2016) The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12(3):547–564. https://doi.org/10.1080/15548627.2016.1140293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hu Y, Reggiori F (2022) Molecular regulation of autophagosome formation. Biochem Soc Trans 50(1):55–69. https://doi.org/10.1042/BST20210819

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kotani T, Kirisako H, Koizumi M, Ohsumi Y, Nakatogawa H (2018) The Atg2-Atg18 complex tethers pre-autophagosomal membranes to the endoplasmic reticulum for autophagosome formation. Proc Natl Acad Sci U S A 115(41):10363–10368. https://doi.org/10.1073/pnas.1806727115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hollenstein DM, Kraft C (2020) Autophagosomes are formed at a distinct cellular structure. Curr Opin Cell Biol 65:50–57. https://doi.org/10.1016/j.ceb.2020.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Geng J, Klionsky DJ (2008) The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep 9(9):859–864. https://doi.org/10.1038/embor.2008.163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noda NN, Fujioka Y, Hanada T, Ohsumi Y, Inagaki F (2013) Structure of the Atg12-Atg5 conjugate reveals a platform for stimulating Atg8-PE conjugation. EMBO Rep 14(2):206–211. https://doi.org/10.1038/embor.2012.208

    Article  CAS  PubMed  Google Scholar 

  20. Martens S, Fracchiolla D (2020) Activation and targeting of ATG8 protein lipidation. Cell Discov 6:23. https://doi.org/10.1038/s41421-020-0155-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tanida I, Ueno T, Kominami E (2008) LC3 and Autophagy. Methods Mol Biol 445:77–88. https://doi.org/10.1007/978-1-59745-157-4_4

    Article  CAS  PubMed  Google Scholar 

  22. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: Cellular and molecular mechanisms. Autophagy 14(2):207–215. https://doi.org/10.1080/15548627.2017.1378838

    Article  CAS  PubMed  Google Scholar 

  23. Runwal G, Stamatakou E, Siddiqi FH, Puri C et al (2019) LC3-positive structures are prominent in autophagy-deficient cells. Sci Rep 9(1):10147. https://doi.org/10.1038/s41598-019-46657-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang Z, Huang J, Geng J, Nair U, Klionsky DJ (2006) Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 17(12):5094–5104. https://doi.org/10.1091/mbc.e06-06-0479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L (2017) The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (review). Int J Mol Med 40(2):271–280. https://doi.org/10.3892/ijmm.2017.3036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ghosh Chowdhury S, Ray R, Karmakar P (2023) Relating aging and autophagy: a new perspective towards the welfare of human health. EXCLI J 22:732–748. https://doi.org/10.17179/excli2023-6300

    Article  PubMed  PubMed Central  Google Scholar 

  27. Schreiber A, Collins BC, Davis C et al (2021) Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation. Mol Cell 81(24):5066–5081e10. https://doi.org/10.1016/j.molcel.2021.10.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kraft C, Kijanska M, Kalie E et al (2012) Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J 31(18):3691–3703. https://doi.org/10.1038/emboj.2012.225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Keil E, Höcker R, Schuster M et al (2013) Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. Cell Death Differ 20(2):321–332. https://doi.org/10.1038/cdd.2012.129

    Article  CAS  PubMed  Google Scholar 

  30. Feng X, Zhang H, Meng L et al (2021) Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. Autophagy 17(3):723–742. https://doi.org/10.1080/15548627.2020.1731266

    Article  CAS  PubMed  Google Scholar 

  31. Hosokawa N, Hara T, Kaizuka T et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991. https://doi.org/10.1091/mbc.e08-12-1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zachari M, Ganley IG (2017) The mammalian ULK1 complex and autophagy initiation. Essays Biochem 61(6):585–596. https://doi.org/10.1042/EBC20170021

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. https://doi.org/10.1038/ncb2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lu H, Xiao J, Ke C et al (2019) TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ. Cell Death Dis 10(8):583. https://doi.org/10.1038/s41419-019-1805-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fujiwara N, Usui T, Ohama T, Sato K (2016) Regulation of Beclin 1 protein phosphorylation and autophagy by protein phosphatase 2A (PP2A) and death-associated protein kinase 3 (DAPK3). J Biol Chem 291(20):10858–10866. https://doi.org/10.1074/jbc.M115.704908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McKnight NC, Zhenyu Y (2013) Beclin 1, an essential component and Master Regulator of PI3K-III in Health and Disease. Curr Pathobiol Rep 1(4):231–238. https://doi.org/10.1007/s40139-013-0028-5

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lee B, Park SJ, Lee S et al (2022) Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR. Cell Death Dis 13(7):603. https://doi.org/10.1038/s41419-022-05039-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dibble CC, Cantley LC (2015) Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25(9):545–555. https://doi.org/10.1016/j.tcb.2015.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Di Malta C, Cinque L, Settembre C (2019) Transcriptional regulation of Autophagy: mechanisms and Diseases. Front Cell Dev Biol 7:114. https://doi.org/10.3389/fcell.2019.00114

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cui Z, Napolitano G, de Araujo MEG et al (2023) Structure of the lysosomal mTORC1-TFEB-Rag-ragulator megacomplex. Nature 614(7948):572–579. https://doi.org/10.1038/s41586-022-05652-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dossou AS, Basu A (2019) The emerging roles of mTORC1 in Macromanaging Autophagy. Cancers (Basel) 11(10):1422. https://doi.org/10.3390/cancers11101422

    Article  CAS  PubMed  Google Scholar 

  42. Chang YY, Neufeld TP (2009) An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 20(7):2004–2014. https://doi.org/10.1091/mbc.e08-12-1250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Manzoni C, Mamais A, Dihanich S et al (2018) mTOR Independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition. Biosci Rep 38(2):BSR20171669. https://doi.org/10.1042/BSR20171669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tamargo-Gómez I, Mariño G (2018) AMPK: Regulation of Metabolic dynamics in the Context of Autophagy. Int J Mol Sci 19(12):3812. https://doi.org/10.3390/ijms19123812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Backer JM (2016) The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem J 473(15):2251–2271. https://doi.org/10.1042/BCJ20160170

    Article  CAS  PubMed  Google Scholar 

  46. Altomare DA, Wang HQ, Skele KL et al (2004) AKT and mTOR phosphorylation is frequently detected in Ovarian cancer and can be targeted to disrupt ovarian Tumor cell growth. Oncogene 23(34):5853–5857. https://doi.org/10.1038/sj.onc.1207721

    Article  CAS  PubMed  Google Scholar 

  47. Kudo Y, Sugimoto M, Arias E et al (2020) PKCλ/ι loss induces Autophagy, oxidative phosphorylation, and NRF2 to promote Liver Cancer Progression. Cancer Cell 38(2):247–262e11. https://doi.org/10.1016/j.ccell.2020.05.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Klionsky DJ, Schulman BA (2014) Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol 21(4):336–345. https://doi.org/10.1038/nsmb.2787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tracz M, Bialek W (2021) Beyond K48 and K63: non-canonical protein ubiquitination. Cell Mol Biol Lett 26(1):1. https://doi.org/10.1186/s11658-020-00245-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Manley S, Williams JA, Ding WX (2013) Role of p62/SQSTM1 in liver physiology and pathogenesis. Exp Biol Med (Maywood) 238(5):525–538. https://doi.org/10.1177/1535370213489446

    Article  CAS  PubMed  Google Scholar 

  51. Shin WH, Park JH, Chung KC (2020) The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson’s Disease. BMB Rep 53(1):56–63. https://doi.org/10.5483/BMBRep.2020.53.1.283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bitto A, Lerner CA, Nacarelli T, Crowe E, Torres C, Sell C (2014) P62/SQSTM1 at the interface of aging, autophagy, and Disease. Age (Dordr) 36(3):9626. https://doi.org/10.1007/s11357-014-9626-3

    Article  CAS  PubMed  Google Scholar 

  53. Rider L, Cramer SD (2015) SPOP the mutation. Elife 4:e11760. https://doi.org/10.7554/eLife.11760

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gao K, Shi Q, Liu Y, Wang C (2022) Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven Prostate cancer. Autophagy 18(8):2013–2015. https://doi.org/10.1080/15548627.2022.2062873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Raimondi M, Cesselli D, Di Loreto C, La Marra F, Schneider C, Demarchi F (2019) USP1 (ubiquitin specific peptidase 1) targets ULK1 and regulates its cellular compartmentalization and autophagy. Autophagy 15(4):613–630. https://doi.org/10.1080/15548627.2018.1535291

    Article  CAS  PubMed  Google Scholar 

  56. Kim JH, Seo D, Kim SJ et al (2018) The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation. EMBO Rep 19(4):e44378. https://doi.org/10.15252/embr.201744378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Han SH, Korm S, Han YG et al (2019) GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic Myeloid Leukemia. Autophagy 15(12):2076–2090. https://doi.org/10.1080/15548627.2019.1596492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cao L, Liu X, Zheng B, Xing C, Liu J (2022) Role of K63-linked ubiquitination in cancer. Cell Death Discov 8(1):410. https://doi.org/10.1038/s41420-022-01204-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Han T, Guo M, Gan M, Yu B, Tian X, Wang JB (2018) TRIM59 regulates autophagy through modulating both the transcription and the ubiquitination of BECN1. Autophagy 14(12):2035–2048. https://doi.org/10.1080/15548627.2018.1491493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhan Z, Xie X, Cao H et al (2014) Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of Lung cancer cells through the promotion of TRAF6 ubiquitination. Autophagy 10(2):257–268. https://doi.org/10.4161/auto.27162

    Article  CAS  PubMed  Google Scholar 

  61. Wang G, Gao Y, Li L et al (2012) K63-linked ubiquitination in kinase activation and cancer. Front Oncol 2:5. https://doi.org/10.3389/fonc.2012.00005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen YH, Huang TY, Lin YT et al (2021) VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism. Nat Commun 12(1):1322. https://doi.org/10.1038/s41467-021-21715-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu Z, Chen P, Gao H et al (2014) Ubiquitylation of autophagy receptor optineurin by HACE1 activates selective autophagy for Tumor suppression. Cancer Cell 26(1):106–120. https://doi.org/10.1016/j.ccr.2014.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xia Q, Ali S, Liu L et al (2020) Role of Ubiquitination in PTEN Cellular Homeostasis and its implications in GB Drug Resistance. Front Oncol 10:1569. https://doi.org/10.3389/fonc.2020.01569

    Article  PubMed  PubMed Central  Google Scholar 

  65. Zhai F, Wang J, Yang W, Ye M, Jin X (2022) The E3 ligases in Cervical Cancer and Endometrial Cancer. Cancers (Basel) 14(21):5354. https://doi.org/10.3390/cancers14215354

    Article  CAS  PubMed  Google Scholar 

  66. Lee YR, Chen M, Lee JD et al (2019) Reactivation of PTEN Tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 364(6441):eaau0159. https://doi.org/10.1126/science.aau0159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Boughton AJ, Krueger S, Fushman D (2020) Branching via K11 and K48 Bestows Ubiquitin Chains with a Unique Interdomain Interface and enhanced Affinity for Proteasomal Subunit Rpn1. Structure 28(1):29–43e6. https://doi.org/10.1016/j.str.2019.10.008

    Article  CAS  PubMed  Google Scholar 

  68. Lee MS, Jeong MH, Lee HW et al (2015) PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nat Commun 6:7769. https://doi.org/10.1038/ncomms8769

    Article  CAS  PubMed  Google Scholar 

  69. Xu Y, Wan W (2023) Acetylation in the regulation of autophagy. Autophagy 19(2):379–387. https://doi.org/10.1080/15548627.2022.2062112

    Article  CAS  PubMed  Google Scholar 

  70. Lee IH (2019) Mechanisms and Disease implications of sirtuin-mediated autophagic regulation. Exp Mol Med 51(9):1–11. https://doi.org/10.1038/s12276-019-0302-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee D, Goldberg AL (2013) SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. J Biol Chem 288(42):30515–30526. https://doi.org/10.1074/jbc.M113.489716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim JY, Mondaca-Ruff D, Singh S, Wang Y (2022) SIRT1 and autophagy: implications in Endocrine Disorders. Front Endocrinol (Lausanne) 13:930919. https://doi.org/10.3389/fendo.2022.930919

    Article  PubMed  Google Scholar 

  73. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115(6):727–738. https://doi.org/10.1016/s0092-8674(03)00939-5

    Article  CAS  PubMed  Google Scholar 

  74. Zhang X, Yuan Z, Zhang Y et al (2007) HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 27(2):197–213. https://doi.org/10.1016/j.molcel.2007.05.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cao Y, Luo Y, Zou J et al (2019) Autophagy and its role in gastric cancer. Clin Chim Acta 489:10–20. https://doi.org/10.1016/j.cca.2018.11.028

    Article  CAS  PubMed  Google Scholar 

  76. Sun J, Tai S, Tang L et al (2021) Acetylation Modification during Autophagy and Vascular Aging. Front Physiol 12:598267. https://doi.org/10.3389/fphys.2021.598267

    Article  PubMed  PubMed Central  Google Scholar 

  77. Lin SY, Li TY, Liu Q et al (2012) GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336(6080):477–481. https://doi.org/10.1126/science.1217032

    Article  CAS  PubMed  Google Scholar 

  78. Nie T, Yang S, Ma H et al (2016) Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway. Cell Death Dis 7(12):e2563. https://doi.org/10.1038/cddis.2016.423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Su H, Yang F, Wang Q et al (2017) VPS34 acetylation controls its lipid kinase activity and the initiation of Canonical and non-canonical autophagy. Mol Cell 67(6):907–921e7. https://doi.org/10.1016/j.molcel.2017.07.024

    Article  CAS  PubMed  Google Scholar 

  80. Rao Y, Wan Q, Su H et al (2018) ROS-induced HSP70 promotes cytoplasmic translocation of high-mobility group box 1b and stimulates antiviral autophagy in grass carp kidney cells. J Biol Chem 293(45):17387–17401. https://doi.org/10.1074/jbc.RA118.003840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Marquez RT, Xu L (2012) Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2(2):214–221 PMID: 22485198

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sun T, Ming L, Yan Y, Zhang Y, Xue H (2017) Beclin 1 acetylation impairs the anticancer effect of aspirin in Colorectal cancer cells. Oncotarget 8(43):74781–74790. https://doi.org/10.18632/oncotarget.20367

    Article  PubMed  PubMed Central  Google Scholar 

  83. Huang R, Xu Y, Wan W et al (2015) Deacetylation of nuclear LC3 drives autophagy initiation under Starvation. Mol Cell 57(3):456–466. https://doi.org/10.1016/j.molcel.2014.12.013

    Article  CAS  PubMed  Google Scholar 

  84. Liu J, Bi X, Chen T et al (2015) Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression. Cell Death Dis 6(7):e1827. https://doi.org/10.1038/cddis.2015.193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yu Z, Li H, Zhu J, Wang H, Jin X (2022) The roles of E3 ligases in hepatocellular carcinoma. Am J Cancer Res 12(3):1179–1214 PMID: 35411231

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang T, Zhang X, Li JJ (2002) The role of NF-kappaB in the regulation of cell stress responses. Int Immunopharmacol 2(11):1509–1520. https://doi.org/10.1016/s1567-5769(02)00058-9

    Article  CAS  PubMed  Google Scholar 

  87. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B et al (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11(5):407–420. https://doi.org/10.1016/j.ccr.2007.04.001

    Article  CAS  PubMed  Google Scholar 

  88. Zeng Z, Liang J, Wu L, Zhang H, Lv J, Chen N (2020) Exercise-Induced Autophagy suppresses Sarcopenia through Akt/mTOR and Akt/FoxO3a Signal Pathways and AMPK-Mediated mitochondrial Quality Control. Front Physiol 11:583478. https://doi.org/10.3389/fphys.2020.583478

    Article  PubMed  PubMed Central  Google Scholar 

  89. Yu X, Ma R, Wu Y, Zhai Y, Li S (2018) Reciprocal regulation of metabolic reprogramming and epigenetic modifications in Cancer. Front Genet 9:394. https://doi.org/10.3389/fgene.2018.00394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wan L, Xu K, Wei Y et al (2018) Phosphorylation of EZH2 by AMPK suppresses PRC2 methyltransferase activity and oncogenic function. Mol Cell 69(2):279–291e5. https://doi.org/10.1016/j.molcel.2017.12.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chang C, Su H, Zhang D et al (2015) AMPK-Dependent phosphorylation of GAPDH triggers Sirt1 activation and is necessary for Autophagy upon glucose Starvation. Mol Cell 60(6):930–940. https://doi.org/10.1016/j.molcel.2015.10.037

    Article  CAS  PubMed  Google Scholar 

  92. Shi Y, Shen HM, Gopalakrishnan V, Gordon N (2021) Epigenetic regulation of Autophagy beyond the cytoplasm: a review. Front Cell Dev Biol 9:675599. https://doi.org/10.3389/fcell.2021.675599

    Article  PubMed  PubMed Central  Google Scholar 

  93. Sakamaki JI, Wilkinson S, Hahn M et al (2017) Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol Cell 66(4):517–532e9. https://doi.org/10.1016/j.molcel.2017.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang Y, Huang Y, Liu J et al (2020) Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB. EMBO Rep 21(1):e48335. https://doi.org/10.15252/embr.201948335

    Article  CAS  PubMed  Google Scholar 

  95. Lu L, Li L, Lv X, Wu XS, Liu DP, Liang CC (2011) Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin. Cell Res 21(8):1182–1195. https://doi.org/10.1038/cr.2011.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wei FZ, Cao Z, Wang X et al (2015) Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway. Autophagy 11(12):2309–2322. https://doi.org/10.1080/15548627.2015.1117734

    Article  CAS  PubMed  Google Scholar 

  97. Popova EY, Pinzon-Guzman C, Salzberg AC et al (2016) LSD1-Mediated demethylation of H3K4me2 is required for the transition from late progenitor to differentiated mouse Rod Photoreceptor. Mol Neurobiol 53(7):4563–4581. https://doi.org/10.1007/s12035-015-9395-8

    Article  CAS  PubMed  Google Scholar 

  98. Li L, Liu W, Sun Q, Zhu H, Hong M, Qian S (2021) Decitabine Downregulates TIGAR to Induce Apoptosis and Autophagy in Myeloid Leukemia Cells. Oxid Med Cell Longev. 2021:8877460. https://doi.org/10.1155/2021/8877460

  99. Schnekenburger M, Grandjenette C, Ghelfi J et al (2011) Sustained exposure to the DNA demethylating agent, 2’-deoxy-5-azacytidine, leads to apoptotic cell death in chronic Myeloid Leukemia by promoting differentiation, senescence, and autophagy. Biochem Pharmacol 81(3):364–378. https://doi.org/10.1016/j.bcp.2010.10.013

    Article  CAS  PubMed  Google Scholar 

  100. Yang PM, Lin YT, Shun CT et al (2013) Zebularine inhibits tumorigenesis and stemness of Colorectal cancer via p53-dependent endoplasmic reticulum stress. Sci Rep 3:3219. https://doi.org/10.1038/srep03219

    Article  PubMed  PubMed Central  Google Scholar 

  101. Gao L, Sun X, Zhang Q et al (2018) Histone deacetylase inhibitor trichostatin A and autophagy inhibitor chloroquine synergistically exert anti-tumor activity in H-ras transformed breast epithelial cells. Mol Med Rep 17(3):4345–4350. https://doi.org/10.3892/mmr.2018.8446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bai Y, Chen Y, Chen X et al (2019) Trichostatin A activates FOXO1 and induces autophagy in osteosarcoma. Arch Med Sci 15(1):204–213. https://doi.org/10.5114/aoms.2018.73860

    Article  CAS  PubMed  Google Scholar 

  103. Lee JY, Kuo CW, Tsai SL et al (2016) Inhibition of HDAC3- and HDAC6-Promoted Survivin expression plays an important role in SAHA-Induced autophagy and viability reduction in Breast Cancer cells. Front Pharmacol 7:81. https://doi.org/10.3389/fphar.2016.00081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sun J, Piao J, Li N, Yang Y, Kim KY, Lin Z (2020) Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. FEBS J 287(10):2118–2133. https://doi.org/10.1111/febs.15122

    Article  CAS  PubMed  Google Scholar 

  105. Dong LH, Cheng S, Zheng Z et al (2013) Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma. J Hematol Oncol 6:53. https://doi.org/10.1186/1756-8722-6-53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yang F, Wang F, Liu Y et al (2018) Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative Breast cancer cells. Life Sci 213:149–157. https://doi.org/10.1016/j.lfs.2018.10.034

    Article  CAS  PubMed  Google Scholar 

  107. De U, Son JY, Sachan R et al (2018) A New Synthetic histone deacetylase inhibitor, MHY2256, induces apoptosis and Autophagy Cell Death in Endometrial Cancer cells via p53 acetylation. Int J Mol Sci 19(9):2743. https://doi.org/10.3390/ijms19092743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Xu H, Zhang L, Qian X et al (2019) GSK343 induces autophagy and downregulates the AKT/mTOR signaling pathway in Pancreatic cancer cells. Exp Ther Med 18(4):2608–2616. https://doi.org/10.3892/etm.2019.7845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Li R, Yi X, Wei X et al (2018) EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect Aortic Dissection. Cell Death Dis 9(2):180. https://doi.org/10.1038/s41419-017-0213-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Haebe JR, Bergin CJ, Sandouka T, Benoit YD (2021) Emerging role of G9a in cancer stemness and promises as a therapeutic target. Oncogenesis 10(11):76. https://doi.org/10.1038/s41389-021-00370-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kim TW, Cheon C, Ko SG (2020) SH003 activates autophagic cell death by activating ATF4 and inhibiting G9a under hypoxia in gastric cancer cells. Cell Death Dis 11(8):717. https://doi.org/10.1038/s41419-020-02924-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kim TW, Lee SY, Kim M, Cheon C, Ko SG (2018) Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis 9(9):875. https://doi.org/10.1038/s41419-018-0930-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chao A, Lin CY, Chao AN et al (2017) Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies. Oncotarget 8(43):74434–74450. https://doi.org/10.18632/oncotarget.20158

    Article  PubMed  PubMed Central  Google Scholar 

  114. Wu K, Woo SM, Kwon TK (2020) The histone lysine-specific demethylase 1 inhibitor, SP2509 exerts cytotoxic effects against Renal Cancer cells through downregulation of Bcl-2 and Mcl-1. J Cancer Prev 25(2):79–86. https://doi.org/10.15430/JCP.2020.25.2.79

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wen X, Klionsky DJ (2017) BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function. Autophagy 13(11):1801–1803. https://doi.org/10.1080/15548627.2017.1364334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jang JE, Eom JI, Jeung HK et al (2017) AMPK-ULK1-Mediated Autophagy confers resistance to BET inhibitor JQ1 in Acute Myeloid Leukemia stem cells. Clin Cancer Res 23(11):2781–2794. https://doi.org/10.1158/1078-0432.CCR-16-1903

    Article  CAS  PubMed  Google Scholar 

  117. Li W, Shen X, Feng S, Liu Y, Zhao H et al (2022) BRD4 inhibition by JQ1 protects against LPS-induced cardiac dysfunction by inhibiting activation of NLRP3 inflammasomes. Mol Biol Rep 49(9):8197–8207. https://doi.org/10.1007/s11033-022-07377-2

    Article  CAS  PubMed  Google Scholar 

  118. Luan W, Pang Y, Li R et al (2019) Akt/mTOR-Mediated Autophagy confers Resistance to BET inhibitor JQ1 in Ovarian Cancer. Onco Targets Ther 12:8063–8074. https://doi.org/10.2147/OTT.S220267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the academic fellowship grant from the Department of Science and Technology and Biotechnology, Government of West Bengal.

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  1. Department of Life Science and Biotechnology, Jadavpur University, Kolkata, 700032, India

    Sougata Ghosh Chowdhury & Parimal Karmakar

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Chowdhury, S.G., Karmakar, P. Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach. Mol Biol Rep 51, 3 (2024). https://doi.org/10.1007/s11033-023-08961-w

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