Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma

Leukemia. 2015 Sep;29(9):1918-27. doi: 10.1038/leu.2015.83. Epub 2015 Mar 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum Stress* / drug effects
  • Endoplasmic Reticulum Stress* / genetics
  • Gene Knockdown Techniques
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Interleukin-6 / metabolism
  • Isoenzymes
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Proteasome Inhibitors / pharmacology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism


  • Histone Deacetylase Inhibitors
  • Interleukin-6
  • Isoenzymes
  • Proteasome Inhibitors
  • Repressor Proteins
  • HDAC4 protein, human
  • Histone Deacetylases