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

ER alpha, 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 ER alpha coregulator called CAC1. The CoRNR box of CAC1 was required for the binding to and inactivation of ER alpha. CAC1 also associated with histone demethylase LSD1 and suppressed LSD1-enhanced ER alpha activity. CAC1 impaired recruitment of ER alpha and LSD1 to the ER alpha-responsive promoter, leading to greater H3K9me3 accumulation. This effect was reversed by CAC1 depletion. Finally, CAC1 increased paclitaxel-induced cell death in ER alpha-positive MCF7 cells, which are paclitaxel-resistant. Overall, our study provides the first evidence that CAC1, associated with LSD1, functions as an ER alpha corepressor, implicating a potential antitumor target in ER alpha-positive breast cancer. Structured summary of protein interactions: ER-alpha physically interacts with CAC1 by anti tag coimmunoprecipitation (View Interaction: 1, 2, 3) LSD1 physically interacts with CAC1 by anti tag coimmunoprecipitation (View interaction) CAC1 binds to ER-alpha by pull down (View interaction) CAC1 and ER-alpha colocalize by fluorescence microscopy (View interaction) (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.