Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC)
Abstract
The mainstay of treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) since PCa depends on androgen for growth. Although initially responsive, most tumors progress into androgen-independent/castration-resistant PCa (CRPC).CRPC is lethal and no curative therapy is available. Of the many reasons for the resistance to ADT and newer anti-androgen drugs is the emergence of constitutively active AR variants (AR-Vs) such as AR-V7 that are induced under ADT conditions. Our research goals are to test the hypothesis that the epigenetic regulator KDM4B, a histone lysine demethylase, promotesAR-V7 via alternative splicing, leading to CPRC, and to identify potential therapeutics. Using a multi-disciplinary approach including molecular biology, tumor biology, cell biology, and biochemical method, we showed that KDM4B can be phosphorylated by protein kinase A and binds to splicing machinery in response to ADT condition, leading to generation of ARV7. In collaboration with a partnering principal investigator we also showed that KDM4B inhibitor(s) identified in our lab are effective in suppression of CRPC xenograft growth under castrated condition in preclinical mouse models.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1134726
Entities
People
- Liu Zhi-ping
Organizations
- University of Texas Southwestern Medical Center