How do tumor cells respond to HDAC inhibition?
It is now well recognized that mutations, deregulated expression, and aberrant recruitment of epigenetic readers, writers, and erasers are fundamentally important processes 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 (HDACis) 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 antitumor 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.
Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia.
Andrea
A
Newbold
IMP - Research Institute of Molecular Pathology, Vienna, Austria.
Katrina J
KJ
Falkenberg
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia.|Division of Cancer Medicine, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.
H Miles
HM
Prince
Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Vic., Australia.
Ricky W
RW
Johnstone
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006655:Histone Deacetylases
apoptosis; cell cycle arrest; differentiation; histone deacetylase inhibitor; senescence; tumor immunogenicity