Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation

Abstract

Proteasome inhibitors have become the standard of care for multiple myeloma. Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in multiple myeloma cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical for multiple myeloma, including the super-enhancer controlling the proto-oncogene c-MYC, reduces metabolic activity and cancer cell growth. Epigenetic silencing is attenuated by HDAC3 depletion, suggesting a tumor-suppressive element of this deacetylase in the context of proteasome inhibition. In the absence of treatment, HDAC3 is continuously removed from DNA by the ubiquitin ligase Seven in Absentia Homolog 2 (SIAH2). Overexpression of SIAH2 increases H3K27 acetylation at c-MYC–controlled genes, increases metabolic output, and accelerates cancer cell proliferation. Our studies indicate a novel therapeutic function of proteasome inhibitors in multiple myeloma by reshaping the epigenetic landscape in an HDAC3-dependent manner. As a result, blocking the proteasome effectively antagonizes c-MYC and the genes controlled by this proto-oncogene. Significance: Integrative genomics reveals that a key function of proteasome inhibitors involves limiting the activity of MYC and MYC-dependent genes through epigenetic repression.