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

• Published in: Cell chemical biology Vol. 24; no. 11; pp. 1356 - 1367.e8
• Main Authors: Hanigan, Thomas W., Aboukhatwa, Shaimaa M., Taha, Taha Y., Frasor, Jonna, Petukhov, Pavel A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 16.11.2017
• Subjects: breast cancer; c-Jun N-terminal kinase; Cell Line, Tumor; co-repressor complex; Female; histone deacetylase; histone deacetylase inhibitor; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylases - chemistry; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - metabolism; inhibitor selectivity; Isoenzymes - chemistry; Isoenzymes - genetics; Isoenzymes - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; MCF-7 Cells; Phosphorylation; photoreactive probes; Protein Binding; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; target engagement; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; c-Jun N-terminal kinase; histone deacetylase inhibitor; photoreactive probes; inhibitor selectivity; breast cancer; co-repressor complex; target engagement; histone deacetylase; phosphorylation
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2017.08.015

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. [Display omitted] •Comprehensive analysis of HDAC inhibitor selectivity reveals cell type dependence•HDAC3 activity is divergently regulated by phosphorylation in triple-negative cells•c-Jun N-terminal kinase phosphorylates HDAC3•HDAC3 phosphorylation increases binding and alters selectivity of HDAC inhibitor 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.