Abstract
Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment.
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Abbreviations
- HDAC:
-
Histone deacetylase
- HSP90:
-
heat-shock protein 90
- CTCL:
-
cutaneous T cell lymphoma
- NER:
-
nucleotide excision repair
- VPA:
-
valproic acid
- 3-MA:
-
3-methyladenine
- GFP:
-
green fluorescent protein
- UPS:
-
ubiquitin proteasome system
- KD:
-
knockdown
- WT:
-
wild-type
- NT:
-
non-targeting
- GRP78:
-
glucose-regulated protein 78
- TCP1:
-
T-complex protein 1
- PCNA:
-
proliferating cell nuclear antigen
- PCK1:
-
phosphoenolpyruvate carboxykinase 1
References
Inche AG, La Thangue NB . Chromatin control and cancer-drug discovery: realizing the promise. Drug Discov Today 2006; 11: 97–109.
Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–784.
Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009; 325: 834–840.
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK . Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1: 194–202.
Marks PA, Breslow R . Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 2007; 25: 84–90.
Richon VM, Garcia-Vargas J, Hardwick JS . Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 2009; 280: 201–210.
Duvic M, Vu J . Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs 2007; 16: 1111–1120.
Khan O, La Thangue NB . Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas. Nat Clin Pract Oncol 2008; 5: 714–726.
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R . FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247–1252.
Stimson L, La Thangue NB . Biomarkers for predicting clinical responses to HDAC inhibitors. Cancer Lett 2009; 280: 177–183.
Fotheringham S, Epping MT, Stimson L, Khan O, Wood V, Pezzella F et al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 2009; 15: 57–66.
Chen L, Shinde U, Ortolan TG, Madura K . Ubiquitin-associated (UBA) domains in Rad23 bind ubiquitin and promote inhibition of multi-ubiquitin chain assembly. EMBO Rep 2001; 2: 933–938.
Chen L, Madura K . Rad23 promotes the targeting of proteolytic substrates to the proteasome. Mol Cell Biol 2002; 22: 4902–4913.
Schauber C, Chen L, Tongaonkar P, Vega I, Lambertson D, Potts W et al. Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature 1998; 391: 715–718.
Khan O, Fotheringham S, Wood V, Stimson L, Zhang C, Pezzella F et al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc Natl Acad Sci USA 2010; 107: 6532–6537.
Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109: 31–39.
Shao Y, Gao Z, Marks PA, Jiang X . Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 2004; 101: 18030–18035.
Stimson L, Wood V, Khan O, Fotheringham S, La Thangue NB . HDAC inhibitor-based therapies and haematological malignancy. Ann Oncol 2009; 20: 1293–1302.
Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X . Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci USA 2012; 109: 6561–6565.
Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y . Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 1998; 23: 33–42.
Seglen PO, Gordon PB . 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 1982; 79: 1889–1892.
Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P . Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000; 275: 992–998.
Camus S, Menendez S, Fernandes K, Kua N, Liu G, Xirodimas DP et al. The p53 isoforms are differentially modified by Mdm2. Cell Cycle 2012; 11: 1646–1655.
Bence NF, Bennett EJ, Kopito RR . Application and analysis of the GFPu family of ubiquitin-proteasome system reporters. Methods Enzymol 2005; 399: 481–490.
Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A et al. HDAC6 is a microtubule-associated deacetylase. Nature 2002; 417: 455–458.
Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007; 447: 859–863.
Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 2010; 29: 969–980.
Valenzuela-Fernandez A, Cabrero JR, Serrador JM, Sanchez-Madrid F . HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol 2008; 18: 291–297.
Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005; 18: 601–607.
Posokhova E, Song H, Belcastro M, Higgins L, Bigley LR, Michaud NA et al. Disruption of the chaperonin containing TCP-1 function affects protein networks essential for rod outer segment morphogenesis and survival. Mol Cell Proteomics 2011; 10: M110 000570.
Lisby M, Barlow JH, Burgess RC, Rothstein R . Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 2004; 118: 699–713.
Trepel J, Mollapour M, Giaccone G, Neckers L . Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10: 537–549.
Kroemer G, Marino G, Levine B . Autophagy and the integrated stress response. Mol Cell 2010; 40: 280–293.
Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell 2008; 132: 27–42.
Kimmelman AC . The dynamic nature of autophagy in cancer. Genes Dev 2011; 25: 1999–2010.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.
Mathew R, Karantza-Wadsworth V, White E . Role of autophagy in cancer. Nat Rev Cancer 2007; 7: 961–967.
Degtyarev M, De Maziere A, Orr C, Lin J, Lee BB, Tien JY et al. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 2008; 183: 101–116.
Dang CV . Antimalarial therapy prevents Myc-induced lymphoma. J Clin Invest 2008; 118: 15–17.
Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci USA 2010; 107: 14333–14338.
Kraft C, Peter M, Hofmann K . Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 2010; 12: 836–841.
Voorhees PM, Orlowski RZ . The proteasome and proteasome inhibitors in cancer therapy. Annu Rev Pharmacol Toxicol 2006; 46: 189–213.
Boyault C, Gilquin B, Zhang Y, Rybin V, Garman E, Meyer-Klaucke W et al. HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J 2006; 25: 3357–3366.
Moscat J, Diaz-Meco MT . p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 2009; 137: 1001–1004.
Korolchuk VI, Menzies FM, Rubinsztein DC . Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 2010; 584: 1393–1398.
Dikic I, Johansen T, Kirkin V . Selective autophagy in cancer development and therapy. Cancer Res 2010; 70: 3431–3434.
Scroggins BT, Robzyk K, Wang D, Marcu MG, Tsutsumi S, Beebe K et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell 2007; 25: 151–159.
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003; 115: 727–738.
Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J et al. STRING 8—a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 2009; 37 Database issue D412–D416.
Shevchenko A, Tomas H, Havlis J, Olsen JV, Mann M . In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc 2006; 1: 2856–2860.
David Y, Ternette N, Edelmann MJ, Ziv T, Gayer B, Sertchook R et al. E3 ligases determine ubiquitination site and conjugate type by enforcing specificity on E2 enzymes. J Biol Chem 2011; 286: 44104–44115.
Bastian M, Heymann S, Jacomy M . Gephi: an open source software for exploring and manipulating networks. International AAAI Conference on Weblogs and Social Media 2009.
Acknowledgements
This work was supported by grants from CRUK, MRC, LLR and EU. Heidi Olzscha was supported by an EMBO Long-Term Fellowship, and Maria New by a Gordon Pillar Studentship from LLR. We thank Sarah Atkinson for help in preparing the manuscript.
Author contributions
GL, MN, OK, LS, HO and AC performed the experiments. DK and MM assisted with interpretation. NLT conceived and directed the project, and wrote the manuscript.
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New, M., Olzscha, H., Liu, G. et al. A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors. Cell Death Differ 20, 1306–1316 (2013). https://doi.org/10.1038/cdd.2013.47
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