Seminar "Mechanisms of androgen action in hormone-dependent and advanced hormone-refractory prostate cancer" Prof Satoshi INOUE.

Speaker: Prof. Satoshi Inoue

Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University 

Department of Functional Biogerontrogy, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

Title: Mechanisms of androgen action in hormone-dependent and advanced hormone-refractory prostate cancer

Abstract: Androgen signaling is critical in development and progression of prostate cancer (PC). Recent studies revealed that this signaling is still important in advanced castration-resistant PC (CRPC). To clarify androgen signaling network, we isolated collaborating factors for androgen receptor (AR) and genome-wide androgen target genes in PC cells. They include Oct1, ACSL3. APP, 14-3-3zeta and TACC2, isolated by ChIP-clonig, ChIP-chip, and ChIP-seq analyses combined with transcriptome analyses. The integrated high-throughput genomic and epigenetic analyses provide useful information for mechanisms of androgen action and both diagnostic and therapeutic targets in PC as well as CRPC. Especially, these analyses revealed numerous noncoding RNAs such as miRNAs and long noncoding RNAs (lncRNAs). We found androgen-inducible miRs that target TET2, which catalyses the oxidation of methylated cytosine (5-mC) to 5-hydroxymethylated cytosine 5-hmC. TET2 is repressed by androgen and in PCa. Clinical studies revealed that low 5-hmC, decreased expression of TET2, and high expression of the miRs are predictors for poor outcome of PCa patients. Moreover, the miR knockdown impairs tumor growth and results in increased TET2 expression in animal model of PCa. Mechanistically, global 5-hmC modification regulated by these miRs represses FOXA1 activity. Thus, we proposed that 5-hmC is an epigenetic hallmark of PCa progression. Overall, these AR collaborating factors and target genes including short and long ncRNAs plays epigenetic roles and will be new therapeutic and diagnostic targets for cancer.