Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer

摘要

Prostate cancer can be controlled by androgen‐hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. Here, we found the histone demethylase KDM7A which demethylates histone H3K27 to be overexpressed in enzalutamide resistant castration‐resistant prostate cancer cell line C4‐2b, and investigated the molecular mechanism whereby androgen receptor activity is regulated by KDM7A. We engineered AR‐positive LNCaP cells to stably express a short‐hairpin RNA against KDM7A mRNA from a lentiviral vector. By measuring AR downstream gene expression after androgen stimulation, we found that a KDM7A‐deficient cell line showed lower AR downstream gene expression compared to a control cell. KDM7A knock‐down in LNCaP cell line caused decreased cell proliferation. Western blot analysis with modified‐histone antibody revealed that the KDM7A‐knock‐down LNCaP cell line had increased H3K27 di‐methylation. We confirmed KDM7A binding on AR target‐gene promoters after hormone stimulation in chromatin‐immunoprecipitation experiments. And increased H3K27 di‐methylation was observed in KDM7A knock‐down LNCaP stable cell. Treatment with KDM7A inhibitor, TC‐E 5002, reduced proliferation and induced apoptosis of prostate cancer cells. Finally, we observed that the KDM7A protein was significantly upregulated in prostate cancer tissue, and that this difference correlated with the Gleason score. These data suggested that KDM7A is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.