Subunit composition of the Sin3 histone deacetylase complex is altered by histone deacetylase inhibitors

Histone deacetylase inhibitors are currently in clinical development for several types of cancer. However, the mechanisms through which HDAC inhibitors alter gene expression and inhibit cancer progression are poorly understood. HDAC inhibitors catalytically inhibit the activity of HDACs by chelating a zinc molecule in the active site of the HDAC. However, it is not known what the fate of the multisubunit HDAC containing chromatin complexes are after HDAC inhibitor treatment. To address this, we purified the Sin3/HDAC1/2 complex from 293T cells treated with the HDAC inhibitor SAHA. We discovered that SAHA causes the loss of the PHD‐finger containing ING2 subunit from the Sin3/HDAC1/2 chromatin modifying complex. However, total nuclear levels of ING2 did not change after HDAC inhibitor treatment. Furthermore, this dissociation also occurred in vitro with specific HDAC inhibitors. The occupancies of some Sin3/HDAC subunits at target promoters were reduced after SAHA treatment however ING2 occupancy was not changed. Currently we are determining if the dissociation of ING2 from the complex leads to the loss of binding of the Sin3/HDAC complex at target promoters and assessing the downstream consequences on gene expression. This research is supported by the NIH and the American Cancer Society.