Abstract
The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.
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References
Mottet D, Castronovo V . Histone deacetylases: target enzymes for cancer therapy. Clin Exp Metastasis 2008; 25: 183–189.
Nebbioso A, Carafa V, Benedetti R, Altucci L . Trials with ‘epigenetic’ drugs: an update. Mol Oncol 2012; 6: 657–682.
Qiu T, Zhou L, Zhu W, Wang T, Wang J, Shu Y et al. Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future Oncol 2013; 9: 255–269.
Rangwala S, Zhang C, Duvic M . HDAC inhibitors for the treatment of cutaneous T-cell lymphomas. Future Med Chem 2012; 4: 471–486.
Sawas A, Radeski D, O’Connor OA . Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review. Ther Adv Hematol 2015; 6: 202–208.
McDermott J, Jimeno A . Belinostat for the treatment of peripheral T-cell lymphomas. Drugs Today (Barc) 2014; 50: 337–345.
Cheng T, Grasse L, Shah J, Chandra J . Panobinostat, a pan-histone deacetylase inhibitor: rationale for and application to treatment of multiple myeloma. Drugs Today (Barc) 2015; 51: 491–504.
Thurn KT, Thomas S, Moore A, Munster PN . Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol 2011; 7: 263–283.
Peixoto P, Castronovo V, Matheus N, Polese C, Peulen O, Gonzalez a et al. HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells. Cell Death Differ 2012; 19: 1239–1252.
Fan J, Lou B, Chen W, Zhang J, Lin S, Lv F et al. Down-regulation of HDAC5 inhibits growth of human hepatocellular carcinoma by induction of apoptosis and cell cycle arrest. Tumour Biol 2014; 35: 11523–11532.
He P, Liang J, Shao T, Guo Y, Hou Y, Li Y . HDAC5 promotes colorectal cancer cell proliferation by up-regulating DLL4 expression. Int J Clin Exp Med 2015; 8: 6510–6516.
Liu Q, Zheng J-M, Chen J-K, Yan X-L, Chen H-M, Nong W-X et al. Histone deacetylase 5 promotes the proliferation of glioma cells by upregulation of Notch 1. Mol Med Rep 2014; 10: 2045–2050.
Liu J, Gu J, Feng Z, Yang Y, Zhu N, Lu W et al. Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. J Transl Med 2016; 14: 7.
Zhang L, Wang K, Lei Y, Li Q, Nice EC, Huang C . Redox signaling: potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic Biol Med 2015; 89: 452–465.
Urbich C, Rössig L, Kaluza D, Potente M, Boeckel J-N, Knau A et al. HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells. Blood 2009; 113: 5669–5679.
Held NM, Houtkooper RH . Mitochondrial quality control pathways as determinants of metabolic health. BioEssays 2015; 37: 867–876.
Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV . in vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int 1998; 53: 394–401.
Ma P, Xiao H, Yu C, Liu J, Cheng Z, Song H et al. Enhanced cisplatin chemotherapy by iron oxide nanocarrier-mediated generation of highly toxic reactive oxygen species. Nano Lett 2017; 17: 928–937.
Harris IS, Brugge JS . Cancer: the enemy of my enemy is my friend. Nature 2015; 527: 170–171.
Mailloux RJ, Harper M-E . Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med 2011; 51: 1106–1115.
Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P . Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2011; 2: 49.
Zhao Y, Butler EB, Tan M . Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis 2013; 4: e532.
Kurihara Y, Kanki T, Aoki Y, Hirota Y, Saigusa T, Uchiumi T et al. Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem 2012; 287: 3265–3272.
Gammoh N, Marks PA, Jiang X . Curbing autophagy and histone deacetylases to kill cancer cells. Autophagy 2012; 8: 1521–1522.
Yang ZJ, Chee CE, Huang S, Sinicrope FA . The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 2011; 10: 1533–1541.
Ahrens TD, Timme S, Ostendorp J, Bogatyreva L, Hoeppner J, Hopt UT et al. Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity. Lab Invest 2016; 96: 307–316.
Lenaz G, Baracca A, Barbero G, Bergamini C, Dalmonte ME, Del Sole M et al. Mitochondrial respiratory chain super-complex I-III in physiology and pathology. Biochim Biophys Acta 2010; 1797: 633–640.
Chekhun VF, Lukyanova NY, Burlaka АP, Bezdenezhnykh NA, Shpyleva SI, Tryndyak VP et al. Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin. Int J Oncol 2013; 43: 1481–1486.
Buranrat B, Connor JR . Cytoprotective effects of ferritin on doxorubicin-induced breast cancer cell death. Oncol Rep 2015; 34: 2790–2796.
Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 2011; 126: 63–71.
Arriaga JM, Greco A, Mordoh J, Bianchini M . Metallothionein 1G and zinc sensitize human colorectal cancer cells to chemotherapy. Mol Cancer Ther 2014; 13: 1369–1381.
Margalit O, Simon AJ, Yakubov E, Puca R, Yosepovich A, Avivi C et al. Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function. Int J Cancer 2012; 131: E562–E568.
Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM . An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 2015; 162: 540–551.
Allen EL, Ulanet DB, Pirman D, Mahoney CE, Coco J, Si Y et al. Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep 2016; 17: 876–890.
Patel D, Menon D, Bernfeld E, Mroz V, Kalan S, Loayza D et al. Aspartate rescues S-phase arrest caused by suppression of lutamine utilization in KRas-driven cancer cells. J Biol Chem 2016; 291: 9322–9329.
Ratnikov B, Aza-Blanc P, Ronai ZA, Smith JW, Osterman AL, Scott DA . Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma. Oncotarget 2015; 6: 7379–7389.
Jang M, Kim SS, Lee J . Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 2013; 45: e45.
Gaude E, Frezza C . Defects in mitochondrial metabolism and cancer. Cancer Metab 2014; 2: 10.
Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN . Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 2004; 24: 8467–8476.
Sag CM, Santos CXC, Shah AM . Redox regulation of cardiac hypertrophy. J Mol Cell Cardiol 2014; 73: 103–111.
Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A . Loss of HDAC5 impairs memory function: implications for Alzheimer’s disease. J Alzheimers Dis 2013; 33: 35–44.
Zhu X, Su B, Wang X, Smith MA, Perry G . Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 2007; 64: 2202–2210.
McCord MC, Aizenman E . The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front Aging Neurosci 2014; 6: 77.
Altamura S, Muckenthaler MU . Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 2009; 16: 879–895.
Di Domenico F, Barone E, Perluigi M, Butterfield DA . Strategy to reduce free radical species in Alzheimer’s disease: an update of selected antioxidants. Expert Rev Neurother 2015; 15: 19–40.
Grünblatt E, Bartl J, Riederer P . The link between iron, metabolic syndrome, and Alzheimer’s disease. J Neural Transm 2011; 118: 371–379.
Mottet D, Bellahcène A, Pirotte S, Waltregny D, Deroanne C, Lamour V et al. Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res 2007; 101: 1237–1246.
Mottet D, Pirotte S, Lamour V, Hagedorn M, Javerzat S, Bikfalvi A et al. HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene 2009; 28: 243–256.
Deby-Dupont G, Mouithys-Mickalad A, Serteyn D, Lamy M, Deby C . Resveratrol and curcumin reduce the respiratory burst of Chlamydia-primed THP-1 cells. Biochem Biophys Res Commun 2005; 333: 21–27.
Ceusters JD, Mouithys-Mickalad AA, Franck TJ, Derochette S, Vanderplasschen A, Deby-Dupont GP et al. Effect of myeloperoxidase and anoxia/reoxygenation on mitochondrial respiratory function of cultured primary equine skeletal myoblasts. Mitochondrion 2013; 13: 410–416.
Gangolf M, Czerniecki J, Radermecker M, Detry O, Nisolle M, Jouan C et al. Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PLoS One 2010; 5: e13616.
Sounni NE, Cimino J, Blacher S, Primac I, Truong A, Mazzucchelli G et al. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal. Cell Metab 2014; 20: 280–294.
Acknowledgements
The authors thank the GIGA ‘Cell Imaging and Flow Cytometry’, the GIGA ‘Transciptomic ‘ as well as the GIGA ‘Animal’ core facility for technical assistance. This work was supported by grants from the National Fund for Scientific Research (FNRS) (Belgium), TELEVIE, the Centre Anti-Cancéreux, Fonds Léon Frédéricq and Fonds Spéciaux de Recherche près de l’Université de Liège. PP and JC are FNRS-TELEVIE Post Doc. DM is a Research Associate. P DT is Senior Research Associate and LB is Research Director at the National Fund for Scientific Research (FNRS). CP, EH and AB are FNRS-TELEVIE fellows. NM is FRIA fellow.
Author contributions
Conception and design: E Hendrick, P Peixoto, A Blomme, D Mottet; Development of methodology: E Hendrick, P Peixoto, A Blomme, A Mouithys-Mickalad, D Serteyn, L Bettendorff, B Elmoualij, P De Tullio, G Eppe; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): E Hendrick, P Peixoto, A Blomme, N Matheus, C Polese, J Cimino, A Frère, A Mouithys-Mickalad, P De Tullio, D Mottet; Analysis and interpretation of data (for example, statistical analysis, biostatistics, computational analysis): E Hendrick, P Peixoto, A Blomme, N Matheus, J Cimino, A Mouithys-Mickalad, P De Tullio, G Eppe, F Dequiedt, D Mottet; Writing, review, and/or revision of the manuscript: E Hendrick, P Peixoto, A Blomme, F Dequiedt, V Castronovo, D Mottet; Administrative, technical, or material support (that is, reporting or organizing data, constructing databases): E Hendrick, P Peixoto, A Blomme, N Matheus, C Polese, J Cimino, A Frère, G Eppe, D Mottet; Study supervision: E Hendrick, P Peixoto, V Castronovo, D Mottet.
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Hendrick, E., Peixoto, P., Blomme, A. et al. Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition. Oncogene 36, 4859–4874 (2017). https://doi.org/10.1038/onc.2017.103
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DOI: https://doi.org/10.1038/onc.2017.103
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