Histone methyl-transferases and demethylases in the autophagy regulatory network: the emerging role of KDM1A/LSD1 demethylase

ABSTRACT Macroautophagy/autophagy is a physiological mechanism that is essential for the maintenance of cellular homeostasis and stress adaptation. Defective autophagy is associated with many human diseases, including cancer and neurodegenerative disorders. The emerging implication of epigenetic events in the control of the autophagic process opens new avenues of investigation and offers the opportunity to develop novel therapeutic strategies in diseases associated with dysfunctional autophagy-lysosomal pathways. Accumulating evidence reveals that several methyltransferases and demethylases are essential regulators of autophagy, and recent studies have led to the identification of the lysine demethylase KDM1A/LSD1 as a promising drug target. KDM1A/LSD1 modulates autophagy at multiple levels, participating in the transcriptional control of several downstream effectors. This review summarizes our current understanding of the role of KDM1A/LSD1 in the autophagy regulatory network.

[1]  B. Majello,et al.  Targeting Histone Demethylase LSD1/KDM1a in Neurodegenerative Diseases , 2018, Journal of experimental neuroscience.

[2]  S. Tooze,et al.  Autophagy pathway: Cellular and molecular mechanisms , 2018, Autophagy.

[3]  Lin Chen,et al.  Inhibition of H3K4 demethylation induces autophagy in cancer cell lines. , 2017, Biochimica et biophysica acta. Molecular cell research.

[4]  D. Katz,et al.  Neuroepigenetic mechanisms in disease , 2017, Epigenetics & Chromatin.

[5]  Kirsten A. Porter-Stransky,et al.  LSD1 protects against hippocampal and cortical neurodegeneration , 2017, Nature Communications.

[6]  B. Majello,et al.  Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A. , 2017, Biochimica et biophysica acta. Gene regulatory mechanisms.

[7]  Li‐yu Lee,et al.  Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies , 2017, Oncotarget.

[8]  S. Amente,et al.  Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway , 2017, Oncogene.

[9]  J. Kemper,et al.  A postprandial FGF19‐SHP‐LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy , 2017, The EMBO journal.

[10]  A. Eid,et al.  Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases , 2017, Oxidative medicine and cellular longevity.

[11]  S. Lowe,et al.  Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function , 2017, Molecular cell.

[12]  J. Kim,et al.  Regulation of hypoxia responses by flavin adenine dinucleotide‐dependent modulation of HIF‐1α protein stability , 2017, The EMBO journal.

[13]  Q. Rao,et al.  Identification of JL1037 as a novel, specific, reversible lysine-specific demethylase 1 inhibitor that induce apoptosis and autophagy of AML cells , 2017, Oncotarget.

[14]  M. Dong,et al.  Phosphorylation of LSD1 by PLK1 promotes its chromatin release during mitosis , 2017, Cell & Bioscience.

[15]  S. P. Andrews,et al.  Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities , 2017, Neuron.

[16]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[17]  C. Santoni,et al.  Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells , 2017, Cellular Oncology.

[18]  Wei-Chih Liao,et al.  Statin Decreases Helicobacter pylori Burden in Macrophages by Promoting Autophagy , 2017, Front. Cell. Infect. Microbiol..

[19]  Jianhua Zheng,et al.  Lysine-Specific Demethylase 1 (LSD1) Inhibitor S2101 Induces Autophagy via the AKT/mTOR Pathway in SKOV3 Ovarian Cancer Cells , 2016, Medical science monitor : international medical journal of experimental and clinical research.

[20]  A. Ardekani,et al.  Role of Epigenetics in Biology and Human Diseases , 2016, Iranian biomedical journal.

[21]  Wei Zhang,et al.  Histone H2B monoubiquitination is a critical epigenetic switch for the regulation of autophagy , 2016, Nucleic acids research.

[22]  Asserewou Etekpo,et al.  Effects of Metformin and a Mammalian Target of Rapamycin (mTOR) ATP-Competitive Inhibitor on Targeted Metabolomics in Pancreatic Cancer Cell Line. , 2016, Metabolomics : open access.

[23]  D. Rubinsztein,et al.  Transcriptional regulation of mammalian autophagy at a glance , 2016, Journal of Cell Science.

[24]  Qianfa Long,et al.  Downregulation of KDM4A Suppresses the Survival of Glioma Cells by Promoting Autophagy , 2016, Journal of Molecular Neuroscience.

[25]  T. Somervaille,et al.  LSD1: biologic roles and therapeutic targeting , 2016, Epigenomics.

[26]  N. Ktistakis,et al.  Digesting the Expanding Mechanisms of Autophagy. , 2016, Trends in cell biology.

[27]  Y. Dou,et al.  MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition. , 2016, Cell reports.

[28]  Kyoung-Jae Won,et al.  AMPK–SKP2–CARM1 signalling cascade in transcriptional regulation of autophagy , 2016, Nature.

[29]  E. White.  Autophagy and p53. , 2016, Cold Spring Harbor perspectives in medicine.

[30]  A. Kornblihtt,et al.  Histone methylation, alternative splicing and neuronal differentiation , 2016, Neurogenesis.

[31]  D. Sabatini,et al.  Sestrin2 is a leucine sensor for the mTORC1 pathway , 2016, Science.

[32]  R. Leng,et al.  UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation , 2015, Oncotarget.

[33]  T. Ushijima,et al.  Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway , 2015, Autophagy.

[34]  Han Liu,et al.  Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation , 2015, Autophagy.

[35]  G. Perini,et al.  Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma , 2015, Oncotarget.

[36]  Jigang Wang,et al.  Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways , 2015, Autophagy.

[37]  R. Kalb,et al.  Regulation of Protein Quality Control by UBE4B and LSD1 through p53-Mediated Transcription , 2015, PLoS biology.

[38]  B. Joseph,et al.  Rph1/KDM4 Mediates Nutrient-Limitation Signaling that Leads to the Transcriptional Induction of Autophagy , 2015, Current Biology.

[39]  Xiao-Dong Zhang,et al.  The Selective Activation of p53 Target Genes Regulated by SMYD2 in BIX-01294 Induced Autophagy-Related Cell Death , 2015, PloS one.

[40]  Takayoshi Suzuki,et al.  NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect , 2014, Oncotarget.

[41]  Pei-Ming Yang,et al.  S-Adenosyl-l-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells , 2014, Anti-cancer drugs.

[42]  P. Sorensen,et al.  Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival , 2014, Nature Communications.

[43]  Wei Wang,et al.  Sestrins inhibit mTORC1 kinase activation through the GATOR complex. , 2014, Cell reports.

[44]  G. Yoon,et al.  Transcriptional regulation of autophagy by an FXR/CREB axis , 2014, Nature.

[45]  Jing Liang,et al.  Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development. , 2014, Molecular cell.

[46]  John H. Zhang,et al.  Hypoxia Induces Autophagic Cell Death through Hypoxia-Inducible Factor 1α in Microglia , 2014, PloS one.

[47]  A. Brunet,et al.  FOXO transcription factors: key regulators of cellular quality control. , 2014, Trends in biochemical sciences.

[48]  Harukazu Suzuki,et al.  Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. , 2014, The Journal of infectious diseases.

[49]  O. Hermanson,et al.  Cracking the survival code , 2014, Autophagy.

[50]  A. Bergmann,et al.  UTX coordinates steroid hormone-mediated autophagy and cell death , 2013, Nature Communications.

[51]  B. Joseph,et al.  The return of the nucleus: transcriptional and epigenetic control of autophagy , 2013, Nature Reviews Molecular Cell Biology.

[52]  S. Amente,et al.  The histone LSD1 demethylase in stemness and cancer transcription programs. , 2013, Biochimica et biophysica acta.

[53]  Dong Eun Kim,et al.  BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production , 2013, Autophagy.

[54]  T. Gress,et al.  Epigenetic Regulation of Autophagy by the Methyltransferase G9a , 2013, Molecular and Cellular Biology.

[55]  O. Hermanson,et al.  The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy , 2013, Nature.

[56]  A. Sidow,et al.  Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. , 2013, Genes & development.

[57]  Yong-Yeon Cho,et al.  Autophagy and Cellular Senescence Mediated by Sox2 Suppress Malignancy of Cancer Cells , 2013, PloS one.

[58]  C. Schofield,et al.  Mechanisms of human histone and nucleic acid demethylases. , 2012, Current opinion in chemical biology.

[59]  J. Whetstine,et al.  Histone lysine methylation dynamics: establishment, regulation, and biological impact. , 2012, Molecular cell.

[60]  Sungpil Yoon,et al.  Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. , 2012, International journal of oncology.

[61]  Yong Chen,et al.  MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB , 2012, Autophagy.

[62]  L. Pfeffer,et al.  The histone H3 lysine 56 acetylation pathway is regulated by target of rapamycin (TOR) signaling and functions directly in ribosomal RNA biogenesis , 2012, Nucleic acids research.

[63]  P. Marks,et al.  Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death , 2012, Proceedings of the National Academy of Sciences.

[64]  E. White.  Role of autophagy in cancer , 2012 .

[65]  M. Nakao,et al.  FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure , 2012, Nature Communications.

[66]  Zhaohui S. Qin,et al.  FOXP3 orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting MOF and causing displacement of PLU-1. , 2011, Molecular cell.

[67]  A. Ballabio,et al.  Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. , 2011, Human molecular genetics.

[68]  E. Morselli,et al.  p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200 , 2011, Cell cycle.

[69]  Xuejun Wang,et al.  Autophagy and p62 in Cardiac Proteinopathy , 2011, Circulation research.

[70]  Andrea Ballabio,et al.  TFEB Links Autophagy to Lysosomal Biogenesis , 2011, Science.

[71]  J. C. Belmonte,et al.  LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells , 2011, Nature Cell Biology.

[72]  Christopher M. Dobson,et al.  Clusterin facilitates in vivo clearance of extracellular misfolded proteins , 2011, Cellular and Molecular Life Sciences.

[73]  S. Pomeroy,et al.  UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53 , 2011, Nature Medicine.

[74]  B. Viollet,et al.  AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 , 2011, Nature Cell Biology.

[75]  B. Ponder,et al.  Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. , 2011, Cancer research.

[76]  H. Virgin,et al.  Autophagy in immunity and inflammation , 2011, Nature.

[77]  O. Dovey,et al.  Lysine-Specific Demethylase 1 Regulates the Embryonic Transcriptome and CoREST Stability , 2010, Molecular and Cellular Biology.

[78]  M. Musri,et al.  Histone Demethylase LSD1 Regulates Adipogenesis* , 2010, The Journal of Biological Chemistry.

[79]  I. Talianidis,et al.  Lysine methylation regulates E2F1-induced cell death. , 2010, Molecular cell.

[80]  Simon Watkins,et al.  An Autophagy-Enhancing Drug Promotes Degradation of Mutant α1-Antitrypsin Z and Reduces Hepatic Fibrosis , 2010, Science.

[81]  Xingzhi Xu,et al.  LSD1 is required for chromosome segregation during mitosis. , 2010, European journal of cell biology.

[82]  S. Lippman,et al.  Open Access RESEARCH , 2010 .

[83]  Luyang Sun,et al.  LSD1 Is a Subunit of the NuRD Complex and Targets the Metastasis Programs in Breast Cancer , 2009, Cell.

[84]  Valerio Embrione,et al.  A Gene Network Regulating Lysosomal Biogenesis and Function , 2009, Science.

[85]  E. Morselli,et al.  Stimulation of autophagy by the p53 target gene Sestrin2 , 2009, Cell cycle.

[86]  Z. Elazar,et al.  The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes , 2008, Journal of Cell Science.

[87]  D. Ginsberg,et al.  E2F1 regulates autophagy and the transcription of autophagy genes , 2008, Oncogene.

[88]  G. Semenza,et al.  Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia* , 2008, Journal of Biological Chemistry.

[89]  F. Forneris,et al.  LSD1: oxidative chemistry for multifaceted functions in chromatin regulation. , 2008, Trends in biochemical sciences.

[90]  E. Avvedimento,et al.  DNA Oxidation as Triggered by H3K9me2 Demethylation Drives Estrogen-Induced Gene Expression , 2008, Science.

[91]  T. Veenstra,et al.  Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases , 2007, Proceedings of the National Academy of Sciences.

[92]  C. Sette,et al.  Dynamic Regulation of Histone H3 Methylation at Lysine 4 in Mammalian Spermatogenesis1 , 2007, Biology of reproduction.

[93]  Min Gyu Lee,et al.  Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination , 2007, Science.

[94]  Min Gyu Lee,et al.  p53 is regulated by the lysine demethylase LSD1 , 2007, Nature.

[95]  Xinbin Chen,et al.  The Lysine-specific Demethylase 1 Is Required for Cell Proliferation in Both p53-dependent and -independent Manners* , 2007, Journal of Biological Chemistry.

[96]  S. Schreiber,et al.  Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. , 2007, Nature chemical biology.

[97]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[98]  E. May,et al.  Expression of C-terminal deleted p53 isoforms in neuroblastoma , 2006, Nucleic acids research.

[99]  Kevin M. Ryan,et al.  DRAM, a p53-Induced Modulator of Autophagy, Is Critical for Apoptosis , 2006, Cell.

[100]  F. Lan,et al.  Regulation of LSD1 histone demethylase activity by its associated factors. , 2005, Molecular cell.

[101]  Min Gyu Lee,et al.  An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation , 2005, Nature.

[102]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[103]  F. Forneris,et al.  Histone demethylation catalysed by LSD1 is a flavin‐dependent oxidative process , 2005, FEBS letters.

[104]  Yang Shi,et al.  Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 , 2004, Cell.

[105]  Yang Shi,et al.  Coordinated histone modifications mediated by a CtBP co-repressor complex , 2003, Nature.

[106]  R. Schneider,et al.  Lateral Thinking: How Histone Modifications Regulate Gene Expression. , 2016, Trends in genetics : TIG.

[107]  R. Labbe,et al.  Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. , 2013, American journal of translational research.

[108]  E. Li,et al.  The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation , 2009, Nature Genetics.