Abstract
The class-I histone deacetylases (HDACs) HDAC1 and HDAC2 belong to a family of 11 zinc-dependent human HDACs and are overexpressed in many cancers. Inhibitors of these HDACs now in clinical trials show activity against several types of cancers. This review is focused on recent advances in both clinical and preclinical efforts to understand the basis for the actions of HDACis, with emphasis on implications for rational combinations with conventional or other targeted agents. We will address new perspectives on the molecular mechanisms by which HDACs act and how these actions relate to cancer. We will also review new evidence showing that HDACs are direct intracellular targets of the potent sphingolipid mediator S1P, the first identified endogenous nuclear regulator of these enzymes, linking sphingolipid metabolism in the nucleus to remodeling of chromatin and epigenetic regulation of gene expression. Understanding how endogenous molecules regulate HDAC activity in vivo may facilitate the search for safer and more effective anticancer drugs capable of interfering with HDAC functions in a highly specific manner.
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Acknowledgements
We apologize to authors whose work has not been cited here owing to space limitations. This work was supported by R01CA61774 (SS) R37GM043880 (SS), R01AI50094 (SS), 1U19AI077435 (SS),), R01AI50094 (SS), 1U19AI077435 (SS), RO1CA93738-05 (SG), CA100866 (SG), 1P50CA142509 (SG), RC2CA148431 (SG), 1P50CA130805 (SG), 1R21CA137823, the Leukemia and Lymphoma Society of America 6181-10 (SG), the V Foundation and the Multiple Myeloma Research Foundation (SG).
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Spiegel, S., Milstien, S. & Grant, S. Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene 31, 537–551 (2012). https://doi.org/10.1038/onc.2011.267
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EGFR‐vIII downregulated H2AZK4/7AC though the PI3K/AKT‐HDAC2 axis to regulate cell cycle progression
Clinical and Translational Medicine (2020)
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Maternal exposure to perfluorooctanoic acid (PFOA) causes liver toxicity through PPAR-α pathway and lowered histone acetylation in female offspring mice
Environmental Science and Pollution Research (2019)
