Negative regulation of ERα by a novel protein CAC1 through association with histone demethylase LSD1.

ERα, a critical transcriptional factor for breast cancer proliferation, is regulated by a complex binding repertoire that includes coactivators and corepressors. Here, we identified a novel class of ERα coregulator called CAC1. The CoRNR box of CAC1 was required for the binding to and inactivation of ERα. CAC1 also associated with histone demethylase LSD1 and suppressed LSD1-enhanced ERα activity. CAC1 impaired recruitment of ERα and LSD1 to the ERα-responsive promoter, leading to greater H3K9me3 accumulation. This effect was reversed by CAC1 depletion. Finally, CAC1 increased paclitaxel-induced cell death in ERα-positive MCF7 cells, which are paclitaxel-resistant. Overall, our study provides the first evidence that CAC1, associated with LSD1, functions as an ERα corepressor, implicating a potential antitumor target in ERα-positive breast cancer.