Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity

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Abstract

Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACis) is unclear. In this study, we developed a method that identified a 3- to 16-fold increase in HDACi selectivity for HDAC3 in triple-negative breast cancer (TNBC) cells in comparison with luminal subtypes that was not predicted by current practice measurements with recombinant proteins. We found this increase was caused by c-Jun N-terminal kinase (JNK) phosphorylation of HDAC3, was independent of HDAC3 complex composition or subcellular localization, and was associated with a 5-fold increase in HDAC3 enzymatic activity. This study points to HDAC3 and the JNK axes as targets in TNBC, highlights how HDAC phosphorylation affects HDACi binding and selectivity, and outlines a method to identify changes in individual HDAC isoforms catalytic activity, applicable to any disease state. Hanigan et al. developed a method to identify relevant HDAC isoforms associated with inhibitor efficacy in breast cancer cells. They found c-Jun N-terminal kinase phosphorylation increases inhibitor binding and selectivity, and causes divergent regulation of HDAC3 in triple-negative versus luminal cells.

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Hanigan, T. W., Aboukhatwa, S. M., Taha, T. Y., Frasor, J., & Petukhov, P. A. (2017). Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity. Cell Chemical Biology, 24(11), 1356-1367.e8. https://doi.org/10.1016/j.chembiol.2017.08.015

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