Molecular Mechanism Of Androgen Induced Transcriptional Process Regulated By Demethylases LSD1and JMJD1A

Posttranslational modifications of histone N-terminal tails such as methylation impact chromatin structure and gene transcription. Nuclear amine oxidase homolog LSD1can promote androgen-receptor-dependent transcription, and its overexpression in prostate tumors correlates significantly with relapse of the tumor during anticancer treatment. JmjC-containing demethylase JMJD1A can regulate the transcriptional activity of androgen receptor by demethylasing H3K9Me2. But their exact mechanisms as coactivators during androgen induced gene expression are not clear. To understand the molecular mechanisms of transcriptional regulation by LSD1or JMJD1A, we used lentiviral vectors carrying LSD1or JMJD1A specific shRNAs to obtain the LSD1or JMJD1A knockdown LNCaP stable cell pools. We found that knockdown of LSD1or JMJD1A decreased the expression of AR induced target genes such as PSA and NKX3.1. Chromatin immunoprecipitation assays revealed that knockdown of LSD1or JMJD1A did not significantly change the recruitment of androgen receptor, RNA polymerase â…¡, CBP, SRC family proteins (including SRC-1and SRC-3), and Brg1. In addition, knockdown of LSD1or JMJD1A did not affect chromatin disruption. Consistent with previous data, knockdown of LSD1or JMJD1A did affected histone demethylation of H3K9me2. Interestingly, we found that knockdown of LSD1affected the recruitment of TRAP220, while knockdown of JMJD1A did not. Our data suggested that LSD1might regulate androgen-receptor-dependent transcription through the control of mediator recruitment.