Abstract
Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM.
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Acknowledgements
This study was supported by ITO Foundation for the Promotion of Medical Science (to SK) and the National Institutes of Health (RO-1 CA 178264). KCA is an American Cancer Society Clinical Research Professor.
Author Contributions
SK designed and performed experiments, analyzed the data and prepared the manuscript; RS and HO designed and performed experiments and analyzed the data; YY, DL, FC, JJ, GB, TH, GG, YT and PGR performed experiments; TH and KCA designed experiments, analyzed the data and prepared the manuscript.
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PGR is a member of advisory board for Celgene, Millennium, Johnson & Johnson, Novartis and Keryx. TH is a consultant for Acetylon Pharmaceuticals. KCA is a member of advisory board for Millennium, Celgene, Gilead, Bristol Myers Squibb, and Sanofi-Aventis and is a scientific founder of Acetylon and Oncopep. The other authors declare no conflict of interest.
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Kikuchi, S., Suzuki, R., Ohguchi, H. et al. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia 29, 1918–1927 (2015). https://doi.org/10.1038/leu.2015.83
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DOI: https://doi.org/10.1038/leu.2015.83
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