HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer.

There are 18 lysine deacetylases, also known as histone deacetylases (HDACs), that remove acetyl groups from histone and non-histone proteins, thereby playing critical roles in numerous biological processes. In many human cancers, HDACs are dysregulated through mutation, altered expression, or inappropriate recruitment to certain loci. However, knowledge of the genomic and transcriptomic alterations and the clinical significance of most HDACs in breast cancer remain incomplete. We used TCGA and METABRIC datasets to perform comprehensive, integrated genomic and transcriptomic analyses of 18 HDAC genes in approximately 3000 primary breast cancers and identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found distinct patterns of copy number alteration and expression for each HDAC in breast cancer subtypes. We demonstrated that HDAC2 and SIRT7 were the most commonly amplified/overexpressed, and SIRT3 was most deleted/underexpressed, particularly in aggressive basal-like breast cancer. Overexpression of HDAC2 was significantly correlated with high tumor grade, positive lymph node status, and poor prognosis. The HDAC inhibitor mocetinostat showed anti-tumor effects in HDAC2-overexpressing basal-like breast cancer lines in vitro. Furthermore, HDAC2 expression was positively correlated with a set of DNA-damage response genes, notably RAD51. We revealed a potential mechanism by which HDAC2 regulates RAD51 expression-by indirect mediation through microRNAs, e.g., miR-182. HDAC inhibitors have emerged as a promising new class of multifunctional anticancer agents. Identifying which breast cancers or patients show HDAC deregulation that contributes to tumor development/progression might enable us to improve target cancer therapy.