New and emerging HDAC inhibitors for cancer treatment
Alison C. West, Ricky W. Johnstone
Alison C. West, Ricky W. Johnstone
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(1):30-39. https://doi.org/10.1172/JCI69738.
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New and emerging HDAC inhibitors for cancer treatment

Abstract

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

Authors

Alison C. West, Ricky W. Johnstone

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Figure 1

The molecular targets of HDACs, downstream cellular pathways, and anticancer outcomes of HDAC inhibition.

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The molecular targets of HDACs, downstream cellular pathways, and antica...
HDAC substrates include histones and nonhistone proteins. Histones are the primary substrates for HDAC1, -2, and -3, while other cellular proteins are targeted by one or more class I and class II HDACs. Some known HDAC targets, downstream molecular changes that occur following HDAC inhibition, and associated biological pathways that mediate antitumor responses are shown. The HDACs, substrates, and molecular responses are color matched to illustrate functional relationships. The best-characterized biological consequences of HDACi treatment of tumor cells are shown on the lowest tier of the diagram. SMC3, structural maintenance of chromosomes 3; GCMa, glial cells missing homolog 1; HAT, histone acetyltransferase; HP1, heterochromatin protein 1.