How do tumor cells respond to HDAC inhibition?

Andrea Newbold, Katrina J. Falkenberg, H. Miles Prince, Ricky W. Johnstone

It is now well recognised that mutations, de-regulated expression and aberrant recruitment of epigenetic readers, writers and erasers is a fundamentally important process in the onset and maintenance of many human tumors. The molecular, biological and biochemical characteristics of a particular class of epigenetic erasers, the histone deacetylases (HDACs), have been extensively studied and small molecule HDAC inhibitors (HDACi) have now been clinically approved for the treatment of human hemopoietic malignancies. This review explores our current understanding of the biological and molecular effects on tumor cells following HDACi-treatment. The predominant responses include induction of tumor cell death and inhibition of proliferation that in experimental models have been linked to therapeutic efficacy. However tumor cell-intrinsic responses to HDACi, including modulating tumor immunogenicity have also been described and may have substantial roles in mediating the anti-tumor effects of HDACi. We posit that the field has failed to fully reconcile the biological consequences of exposure to HDACis with the molecular events that underpin these responses, however progress is being made. Understanding the pleiotrophic activities of HDACis on tumor cells will hopefully fast track the development of more potent and selective HDACi that may be used alone or in combination to improve patient outcomes. This article is protected by copyright. All rights reserved.