Skip to main content
SpringerLink
Log in

Dysregulation of histone deacetylases in carcinogenesis and tumor progression: a possible link to apoptosis and autophagy

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L (2018) Cancer epigenetics: moving forward. PLoS Genet 14:e1007362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36

    Article  CAS  PubMed  Google Scholar 

  3. Chen QW, Zhu XY, Li YY, Meng ZQ (2014) Epigenetic regulation and cancer (review). Oncol Rep 31:523–532

    Article  CAS  PubMed  Google Scholar 

  4. Herceg Z, Ushijima T (2010) Introduction: epigenetics and cancer. Adv Genet 70:1–23

    Article  PubMed  Google Scholar 

  5. Baxter E, Windloch K, Gannon F, Lee JS (2014) Epigenetic regulation in cancer progression. Cell Biosci 4:45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Parbin S, Kar S, Shilpi A, Sengupta D, Deb M, Rath SK, Patra SK (2014) Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer. J Histochem Cytochem 62:11–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311:844–847

    Article  CAS  PubMed  Google Scholar 

  8. Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411

    Article  CAS  PubMed  Google Scholar 

  9. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789:45–57

    Article  CAS  PubMed  Google Scholar 

  10. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Witt O, Deubzer HE, Milde T, Oehme I (2009) HDAC family: what are the cancer relevant targets? Cancer Lett 277:8–21

    Article  CAS  PubMed  Google Scholar 

  12. Chueh AC, Tse JW, Togel L, Mariadason JM (2015) Mechanisms of histone deacetylase inhibitor-regulated gene expression in cancer cells. Antioxid Redox Signal 23:66–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:e1414

    Article  CAS  PubMed  Google Scholar 

  14. Nair SS, Kumar R (2012) Chromatin remodeling in cancer: a gateway to regulate gene transcription. Mol Oncol 6:611–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Glozak MA, Seto E (2007) Histone deacetylases and cancer. Oncogene 26:5420–5432

    Article  CAS  PubMed  Google Scholar 

  16. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784

    Article  CAS  PubMed  Google Scholar 

  17. Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A (1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391:601–605

    Article  CAS  PubMed  Google Scholar 

  18. Kadosh D, Struhl K (1997) Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 89:365–371

    Article  CAS  PubMed  Google Scholar 

  19. Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE (1997) Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89:341–347

    Article  CAS  PubMed  Google Scholar 

  20. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391:597–601

    Article  CAS  PubMed  Google Scholar 

  21. Yamada N, Hamada T, Goto M, Tsutsumida H, Higashi M, Nomoto M, Yonezawa S (2006) MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer. Int J Cancer 119:1850–1857

    Article  CAS  PubMed  Google Scholar 

  22. Augenlicht L, Shi L, Mariadason J, Laboisse C, Velcich A (2003) Repression of MUC2 gene expression by butyrate, a physiological regulator of intestinal cell maturation. Oncogene 22:4983–4992

    Article  CAS  PubMed  Google Scholar 

  23. Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606

    Article  CAS  PubMed  Google Scholar 

  24. Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, Raju GC, Hooi SC (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12:395–404

    Article  CAS  PubMed  Google Scholar 

  25. Huang W, Zhao S, Ammanamanchi S, Brattain M, Venkatasubbarao K, Freeman JW (2005) Trichostatin A induces transforming growth factor beta type II receptor promoter activity and acetylation of Sp1 by recruitment of PCAF/p300 to a Sp1.NF-Y complex. J Biol Chem 280:10047–10054

    Article  CAS  PubMed  Google Scholar 

  26. Zhao Y, Lu S, Wu L, Chai G, Wang H, Chen Y, Sun J, Yu Y, Zhou W, Zheng Q, Wu M, Otterson GA, Zhu WG (2006) Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol 26:2782–2790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhou W, Zhu WG (2009) The changing face of HDAC inhibitor depsipeptide. Curr Cancer Drug Targets 9:91–100

    Article  CAS  PubMed  Google Scholar 

  28. Uo T, Veenstra TD, Morrison RS (2009) Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms. J Neurosci 29:2824–2832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K, Asai T, Ichikawa M, Yamamoto G, Nitta E, Yamagata T, Sasaki K, Mitani K, Ogawa S, Chiba S, Hirai H (2004) AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J Biol Chem 279:15630–15638

    Article  CAS  PubMed  Google Scholar 

  30. Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S, Hormaeche I, McConnell MJ, Pierce S, Cole PA, Licht J, Zelent A (2005) Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol Cell Biol 25:5552–5566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Melnick AM, Westendorf JJ, Polinger A, Carlile GW, Arai S, Ball HJ, Lutterbach B, Hiebert SW, Licht JD (2000) The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Mol Cell Biol 20:2075–2086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feng L, Lin T, Uranishi H, Gu W, Xu Y (2005) Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 25:5389–5395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ito A, Lai CH, Zhao X, Saito S, Hamilton MH, Appella E, Yao TP (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20:1331–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reed SM, Quelle DE (2014) p53 acetylation: regulation and consequences. Cancers (Basel) 7:30–69

    Article  CAS  Google Scholar 

  35. Chen L, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293:1653–1657

    Article  CAS  Google Scholar 

  36. Chen LF, Mu Y, Greene WC (2002) Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J 21:6539–6548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nadiminty N, Lou W, Lee SO, Lin X, Trump DL, Gao AC (2006) Stat3 activation of NF-{kappa}B p100 processing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA 103:7264–7269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307:269–273

    Article  CAS  PubMed  Google Scholar 

  39. Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM, Vassilopoulos A, Ozden O, Park SH, Singh KK, Abdulkadir SA, Spitz DR, Deng CX, Gius D (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17:41–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yu W, Denu RA, Krautkramer KA, Grindle KM, Yang DT, Asimakopoulos F, Hematti P, Denu JM (2016) Loss of SIRT3 provides growth advantage for B cell malignancies. J Biol Chem 291:3268–3279

    Article  CAS  PubMed  Google Scholar 

  41. Wang L, Wang WY, Cao LP (2015) SIRT3 inhibits cell proliferation in human gastric cancer through down-regulation of Notch-1. Int J Clin Exp Med 8:5263–5271

    CAS  PubMed  PubMed Central  Google Scholar 

  42. George J, Nihal M, Singh CK, Zhong W, Liu X, Ahmad N (2016) Pro-proliferative function of mitochondrial sirtuin deacetylase SIRT3 in human melanoma. J Investig Dermatol 136:809–818

    Article  CAS  PubMed  Google Scholar 

  43. Zhang YY, Zhou LM (2012) Sirt3 inhibits hepatocellular carcinoma cell growth through reducing Mdm2-mediated p53 degradation. Biochem Biophys Res Commun 423:26–31

    Article  CAS  PubMed  Google Scholar 

  44. Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L (2002) Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295:1726–1729

    Article  CAS  PubMed  Google Scholar 

  45. Akiyama Y, Watkins N, Suzuki H, Jair KW, van Engeland M, Esteller M, Sakai H, Ren CY, Yuasa Y, Herman JG, Baylin SB (2003) GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol Cell Biol 23:8429–8439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Caslini C, Capo-chichi CD, Roland IH, Nicolas E, Yeung AT, Xu XX (2006) Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene 25:5446–5461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang D, Li W, Zhao R, Chen L, Liu N, Tian Y, Zhao H, Xie M, Lu F, Fang Q, Liang W, Yin F, Li Z (2019) Stabilized peptide HDAC inhibitors derived from HDAC1 substrate H3K56 for the treatment of cancer stem-like cells in vivo. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-1421

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wang ZT, Chen ZJ, Jiang GM, Wu YM, Liu T, Yi YM, Zeng J, Du J, Wang HS (2016) Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells. Cell Signal 28:506–515

    Article  CAS  PubMed  Google Scholar 

  49. Yan W, Liu S, Xu E, Zhang J, Zhang Y, Chen X, Chen X (2013) Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32:599–609

    Article  CAS  PubMed  Google Scholar 

  50. Song Q, Li M, Fan C, Liu Y, Zheng L, Bao Y, Sun L, Yu C, Song Z, Sun Y, Wang G, Huang Y, Li Y (2019) A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4. Sci Rep 9:2350

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ji M, Li Z, Lin Z, Chen L (2018) Antitumor activity of the novel HDAC inhibitor CUDC-101 combined with gemcitabine in pancreatic cancer. Am J Cancer Res 8:2402–2418

    PubMed  PubMed Central  Google Scholar 

  52. Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) EMT: 2016. Cell 166:21–45

    Article  CAS  PubMed  Google Scholar 

  53. Whetstine JR, Ceron J, Ladd B, Dufourcq P, Reinke V, Shi Y (2005) Regulation of tissue-specific and extracellular matrix-related genes by a class I histone deacetylase. Mol Cell 18:483–490

    Article  CAS  PubMed  Google Scholar 

  54. Durst KL, Lutterbach B, Kummalue T, Friedman AD, Hiebert SW (2003) The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain. Mol Cell Biol 23:607–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Peinado H, Ballestar E, Esteller M, Cano A (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 24:306–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Annicotte JS, Iankova I, Miard S, Fritz V, Sarruf D, Abella A, Berthe ML, Noel D, Pillon A, Iborra F, Dubus P, Maudelonde T, Culine S, Fajas L (2006) Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol Cell Biol 26:7561–7574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xu W, Liu H, Liu ZG, Wang HS, Zhang F, Wang H, Zhang J, Chen JJ, Huang HJ, Tan Y, Cao MT, Du J, Zhang QG, Jiang GM (2018) Histone deacetylase inhibitors upregulate Snail via Smad2/3 phosphorylation and stabilization of Snail to promote metastasis of hepatoma cells. Cancer Lett 420:1–13

    Article  CAS  PubMed  Google Scholar 

  58. Crazzolara R, Johrer K, Johnstone RW, Greil R, Kofler R, Meister B, Bernhard D (2002) Histone deacetylase inhibitors potently repress CXCR58 chemokine receptor expression and function in acute lymphoblastic leukaemia. Br J Haematol 119:965–969

    Article  CAS  PubMed  Google Scholar 

  59. Hellebrekers DM, Castermans K, Vire E, Dings RP, Hoebers NT, Mayo KH, Oude Egbrink MG, Molema G, Fuks F, van Engeland M, Griffioen AW (2006) Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res 66:10770–10777

    Article  CAS  PubMed  Google Scholar 

  60. Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV, Dai Y (2012) SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 31:4619–4629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Malik S, Villanova L, Tanaka S, Aonuma M, Roy N, Berber E, Pollack JR, Michishita-Kioi E, Chua KF (2015) SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors. Sci Rep 5:9841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xu J, Zhu W, Xu W, Yao W, Zhang B, Xu Y, Ji S, Liu C, Long J, Ni Q, Yu X (2013) Up-regulation of MBD1 promotes pancreatic cancer cell epithelial-mesenchymal transition and invasion by epigenetic down-regulation of E-cadherin. Curr Mol Med 13:387–400

    CAS  PubMed  Google Scholar 

  63. Chen IC, Chiang WF, Huang HH, Chen PF, Shen YY, Chiang HC (2014) Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis. Mol Cancer 13:254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jiang GM, Wang HS, Zhang F, Zhang KS, Liu ZC, Fang R, Wang H, Cai SH, Du J (2013) Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression. Biochim Biophys Acta 1833:663–671

    Article  CAS  PubMed  Google Scholar 

  65. Zhou W, Ni TK, Wronski A, Glass B, Skibinski A, Beck A, Kuperwasser C (2016) The SIRT2 deacetylase stabilizes slug to control malignancy of basal-like breast cancer. Cell Rep 17:1302–1317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu S, Luo Z, Yu PJ, Xie H, He YW (2016) Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals. Biol Chem 397:75–83

    Article  CAS  PubMed  Google Scholar 

  67. Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Ogawa H, Hamabe A, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Doki Y, Mori M, Ishii H (2015) Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer 113:492–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X, Zhou Y, Wang H, Pan C, Huang W (2014) Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res 20:3434–3445

    Article  CAS  PubMed  Google Scholar 

  69. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443

    Article  PubMed  Google Scholar 

  70. Song C, Zhu S, Wu C, Kang J (2013) Histone deacetylase (HDAC) 10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase (MMP) 2 and 9 expression. J Biol Chem 288:28021–28033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ma P, Pan H, Montgomery RL, Olson EN, Schultz RM (2012) Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development. Proc Natl Acad Sci USA 109:E481–E489

    Article  PubMed  PubMed Central  Google Scholar 

  72. Inoue S, Mai A, Dyer MJ, Cohen GM (2006) Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 66:6785–6792

    Article  CAS  PubMed  Google Scholar 

  73. Escaffit F, Vaute O, Chevillard-Briet M, Segui B, Takami Y, Nakayama T, Trouche D (2007) Cleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progression. Mol Cell Biol 27:554–567

    Article  CAS  PubMed  Google Scholar 

  74. Arunachalam G, Yao H, Sundar IK, Caito S, Rahman I (2010) SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: role of resveratrol. Biochem Biophys Res Commun 393:66–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Giannakou ME, Partridge L (2004) The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 14:408–412

    Article  CAS  PubMed  Google Scholar 

  77. Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321

    Article  CAS  PubMed  Google Scholar 

  78. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015

    Article  CAS  PubMed  Google Scholar 

  79. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116:551–563

    Article  CAS  PubMed  Google Scholar 

  80. Song CL, Tang H, Ran LK, Ko BC, Zhang ZZ, Chen X, Ren JH, Tao NN, Li WY, Huang AL, Chen J (2016) Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3beta/BCL2-associated X protein-dependent apoptotic pathway. Oncogene 35:631–641

    Article  CAS  PubMed  Google Scholar 

  81. Paroni G, Mizzau M, Henderson C, Del Sal G, Schneider C, Brancolini C (2004) Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis. Mol Biol Cell 15:2804–2818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Medina V, Edmonds B, Young GP, James R, Appleton S, Zalewski PD (1997) Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway. Cancer Res 57:3697–3707

    CAS  PubMed  Google Scholar 

  83. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA (2004) Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13:627–638

    Article  CAS  PubMed  Google Scholar 

  84. Subramanian C, Opipari AW Jr, Bian X, Castle VP, Kwok RP (2005) Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 102:4842–4847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang GG, Allis CD, Chi P (2007) Chromatin remodeling and cancer, part I: covalent histone modifications. Trends Mol Med 13:363–372

    Article  CAS  PubMed  Google Scholar 

  86. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18:601–607

    Article  CAS  PubMed  Google Scholar 

  87. Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L, Savas JN, Voisine C, Paganetti P, Tanese N, Hart AC, Yamamoto A, Krainc D (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137:60–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105:3374–3379

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hariharan N, Maejima Y, Nakae J, Paik J, Depinho RA, Sadoshima J (2010) Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 107:1470–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, Bordone L (2009) JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One 4:e8414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, Kepp O, Tasdemir E, Galluzzi L, Shen S, Tailler M, Delahaye N, Tesniere A, De Stefano D, Younes AB, Harper F, Pierron G, Lavandero S, Zitvogel L, Israel A, Baud V, Kroemer G (2010) IKK connects autophagy to major stress pathways. Autophagy 6:189–191

    Article  PubMed  Google Scholar 

  92. Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, Kepp O, Tasdemir E, Galluzzi L, Shen S, Tailler M, Delahaye N, Tesniere A, De Stefano D, Younes AB, Harper F, Pierron G, Lavandero S, Zitvogel L, Israel A, Baud V, Kroemer G (2010) The IKK complex contributes to the induction of autophagy. EMBO J 29:619–631

    Article  CAS  PubMed  Google Scholar 

  93. Comb WC, Cogswell P, Sitcheran R, Baldwin AS (2011) IKK-dependent, NF-kappaB-independent control of autophagic gene expression. Oncogene 30:1727–1732

    Article  CAS  PubMed  Google Scholar 

  94. Ng F, Tang BL (2013) Sirtuins’ modulation of autophagy. J Cell Physiol 228:2262–2270

    Article  CAS  PubMed  Google Scholar 

  95. Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu WG (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12:665–675

    Article  CAS  PubMed  Google Scholar 

  96. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS, Pandey UB, Kaushik S, Tresse E, Lu J, Taylor JP, Cuervo AM, Yao TP (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Oehme I, Linke JP, Bock BC, Milde T, Lodrini M, Hartenstein B, Wiegand I, Eckert C, Roth W, Kool M, Kaden S, Grone HJ, Schulte JH, Lindner S, Hamacher-Brady A, Brady NR, Deubzer HE, Witt O (2013) Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci USA 110:E2592–E2601

    Article  PubMed  PubMed Central  Google Scholar 

  98. Lu W, Zuo Y, Feng Y, Zhang M (2014) SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer. Tumour Biol 35:10699–10705

    Article  CAS  PubMed  Google Scholar 

  99. Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, Steegborn C, Nowak T, Schutkowski M, Pellegrini L, Sansone L, Villanova L, Runci A, Pucci B, Morgante E, Fini M, Mai A, Russo MA, Tafani M (2015) SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy 11:253–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tolkovsky AM (2009) Mitophagy. Biochim Biophys Acta 1793:1508–1515

    Article  CAS  PubMed  Google Scholar 

  101. Meyers-Needham M, Ponnusamy S, Gencer S, Jiang W, Thomas RJ, Senkal CE, Ogretmen B (2012) Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells. EMBO Mol Med 4:78–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nganga R, Oleinik N, Ogretmen B (2018) Mechanisms of ceramide-dependent cancer cell death. Adv Cancer Res 140:1–25

    Article  PubMed  Google Scholar 

  103. Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 187:959–966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, D’Andrilli G, Scambia G, Picchio MC, Alder H, Godwin AK, Croce CM (2003) Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci USA 100:5956–5961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R, Tan IL, Turcan S, Veeriah S, Meng S, Viale A, Schumacher SE, Palmedo P (2014) Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 46:588–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z (2011) Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA 108:16259–16264

    Article  PubMed  PubMed Central  Google Scholar 

  107. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189:211–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Boland ML, Chourasia AH, Macleod KF (2013) Mitochondrial dysfunction in cancer. Front Oncol 3:292

    Article  PubMed  PubMed Central  Google Scholar 

  110. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP (2010) Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol 189:671–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM (2011) PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell 144:689–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tan Z, Luo X, Xiao L, Tang M, Bode AM, Dong Z, Cao Y (2016) The role of PGC1alpha in cancer metabolism and its therapeutic implications. Mol Cancer Ther 15:774–782

    Article  CAS  PubMed  Google Scholar 

  114. Zhang J, Ney PA (2009) Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16:939–946

    Article  CAS  PubMed  Google Scholar 

  115. Shaw J, Yurkova N, Zhang T, Gang H, Aguilar F, Weidman D, Scramstad C, Weisman H, Kirshenbaum LA (2008) Antagonism of E2F-1 regulated Bnip3 transcription by NF-kappaB is essential for basal cell survival. Proc Natl Acad Sci USA 105:20734–20739

    Article  PubMed  PubMed Central  Google Scholar 

  116. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471

    Article  CAS  PubMed  Google Scholar 

  117. Fei P, Wang W, Kim SH, Wang S, Burns TF, Sax JK, Buzzai M, Dicker DT, McKenna WG, Bernhard EJ, El-Deiry WS (2004) Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6:597–609

    Article  CAS  PubMed  Google Scholar 

  118. Chourasia AH, Boland ML, Macleod KF (2015) Mitophagy and cancer. Cancer Metab 3:4

    Article  PubMed  PubMed Central  Google Scholar 

  119. Landes T, Emorine LJ, Courilleau D, Rojo M, Belenguer P, Arnaune-Pelloquin L (2010) The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms. EMBO Rep 11:459–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, Benard G (2013) Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab 17:719–730

    Article  CAS  PubMed  Google Scholar 

  121. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673

    CAS  PubMed  Google Scholar 

  122. Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, Zhu Y, Zhang X, Li L, Zhang L, Sui S, Zhao B, Feng D (2014) ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 15:566–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Wang KZQ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayir H, Kagan VE (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15:1197–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kagan VE, Jiang J, Huang Z, Tyurina YY, Desbourdes C, Cottet-Rousselle C, Dar HH, Verma M, Tyurin VA, Kapralov AA, Cheikhi A, Mao G, Stolz D, St Croix CM, Watkins S, Shen Z, Li Y, Greenberg ML, Tokarska-Schlattner M, Boissan M, Lacombe ML, Epand RM, Chu CT, Mallampalli RK, Bayir H, Schlattner U (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Maceyka M, Harikumar KB, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22:50–60

    Article  CAS  PubMed  Google Scholar 

  126. Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325:1254–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dany M, Ogretmen B (2015) Ceramide induced mitophagy and tumor suppression. Biochim Biophys Acta 1853:2834–2845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sentelle RD, Senkal CE, Jiang W, Ponnusamy S, Gencer S, Selvam SP, Ramshesh VK, Peterson YK, Lemasters JJ, Szulc ZM, Bielawski J, Ogretmen B (2012) Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol 8:831–838

    Article  PubMed  PubMed Central  Google Scholar 

  129. Praharaj PP, Naik PP, Panigrahi DP, Bhol CS, Mahapatra KK, Patra S, Sethi G, Bhutia SK (2018) Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: its implication in cancer therapeutics. Cell Mol Life Sci. https://doi.org/10.1007/s00018-018-2990-x

    Article  PubMed  Google Scholar 

  130. Ogretmen B (2018) Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18:33–50

    Article  CAS  PubMed  Google Scholar 

  131. Xu W, Xu B, Yao Y, Yu X, Shen J (2015) The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production. Biochem Biophys Res Commun 463:545–550

    Article  CAS  PubMed  Google Scholar 

  132. Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338:17–31

    Article  CAS  PubMed  Google Scholar 

  133. West AC, Johnstone RW (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Investig 124:30–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bereshchenko OR, Gu W, Dalla-Favera R (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 32:606–613

    Article  CAS  PubMed  Google Scholar 

  135. Chalkiadaki A, Guarente L (2015) The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 15:608–624

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We convey our thanks to the National Institute of Technology, Rourkela. SP acknowledges DST-INSPIRE, Award reference number (IF180167), Department of Science and Technology, Government of India, for providing fellowship.

Author information

Authors and Affiliations

  1. Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India

    Srimanta Patra, Debasna P. Panigrahi, Prakash P. Praharaj, Chandra S. Bhol, Kewal K. Mahapatra, Soumya R. Mishra, Bishnu P. Behera & Sujit K. Bhutia

  2. PG Department of Botany, Berhampur University, Brahmapur, 760007, India

    Mrutyunjay Jena

Authors
  1. Srimanta Patra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debasna P. Panigrahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prakash P. Praharaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chandra S. Bhol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kewal K. Mahapatra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soumya R. Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bishnu P. Behera
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mrutyunjay Jena
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sujit K. Bhutia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sujit K. Bhutia.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patra, S., Panigrahi, D.P., Praharaj, P.P. et al. Dysregulation of histone deacetylases in carcinogenesis and tumor progression: a possible link to apoptosis and autophagy. Cell. Mol. Life Sci. 76, 3263–3282 (2019). https://doi.org/10.1007/s00018-019-03098-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03098-1

Keywords

Search

Navigation