Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer

Lysine-specific demethylase 5A (KDM5A), an enzyme that removes activating H3K4 di- and trimethylation marks, plays critical roles in controlling transcription and chromatin architecture, yet its biological functions largely remain uncharacterized, particularly in the context of human cancer. In the present study, we found that the KDM5A gene was significantly amplified and over-expressed in various human tumors, including breast cancer. Reducing the expression of KDM5A by shRNA knockdown inhibited proliferation of KDM5A-amplified breast cancer cells. More importantly, we demonstrated that KDM5A over-expression was associated with breast cancer drug resistance. Furthermore, knockdown of KDM5A gene expression altered H3K4 methylation and induced upregulation of CDK inhibitors as well as genes mediating apoptotic cell death. Taken together, our study strongly links KDM5A histone demethylase activity to breast cancer proliferation and drug resistance, and suggests KDM5A is a potential target for breast cancer therapy.