Targeting Histone Demethylase GASC1/JMJD2C/KDM4C as a Novel Therapeutic Strategy in Castration-Resistant Prostate Cancer
Abstract
Prostate cancer is the most common malignancy amongst men worldwide and stands as the second leading cause of cancer deaths. The goal of this study was to assess the therapeutic potential of selective inhibitors for the oncogenic lysine-specific demethylase 4C (KDM4C, also known as GASC1 and JMJD2C) in highly lethal, metastatic castration-resistant prostate cancer (CRPC), for which effective treatments are urgently needed. The GASC1 gene, originally cloned from an amplified region at 9p24 in esophageal cancer cells, is over-expressed in a diverse array of human cancers, including prostate cancer in which it correlates with a poor prognosis for these patients. We found that GASC1 is overexpressed at both the mRNA and protein levels in metastatic CRPCs, and that knockdown of GASC1 inhibits proliferation of CRPC cells in vitro. The GASC1 demethylase plays an essential role in affecting chromatin architecture and gene expression; furthermore, it physically associates with the androgen receptor (AR), a key effector of the survival and growth of CRPCs. Knocking down GASC1 significantly reduced expression of a set of classical and CRPC-specific AR target genes in CRPC cells. Importantly, targeting histone demethylases is an active frontier in epigenetic drug development. Our data indicates that targeting the GASC1 demethylase is a promising strategy to control CRPC or prevent its emergence.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA593287
Entities
People
- Zeng-quan Yang
Organizations
- Wayne State University