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.

中文翻译：

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在三阴性乳腺癌细胞中HDAC3的不同JNK磷酸化决定了HDAC抑制剂的结合和选择性

组蛋白脱乙酰基酶（HDAC）催化活性是通过形成共调节复合物和翻译后修饰来调节的。这些机制是否会在癌症中转化，以及如何影响HDAC抑制剂（HDACis）的结合和选择性尚不清楚。在这项研究中，我们开发了一种方法，该方法与三联阴性乳腺癌（TNBC）细胞中的HDAC3对HDAC3的选择性相比，目前的重组蛋白尚无法预测的管腔亚型提高了3至16倍。我们发现这种增加是由HDAC3的c-Jun N末端激酶（JNK）磷酸化引起的，与HDAC3复杂成分或亚细胞定位无关，并且与HDAC3酶活性增加5倍有关。这项研究指出，HDAC3和JNK轴是TNBC的目标，