The p14ARF tumor suppressor restrains androgen receptor activity and prevents apoptosis in prostate cancer cells. (28th July 2020)

• Record Type: Journal Article
• Authors: Siddiqui, Salma; Libertini, Stephen J.; Lucas, Christopher A.; Lombard, Alan P.; Baek, Han Bit; Nakagawa, Rachel M.; Nishida, Kristine S.; Steele, Thomas M.; Melgoza, Frank U.; Borowsky, Alexander D.; Durbin-Johnson, Blythe P.; Qi, LiHong; Ghosh, Paramita M.; Mudryj, Maria
• Is Part Of: Cancer letters. Volume 483(2020)
• Page Start: 12
• Page End: 21
• Publication Date: 2020-07-28
• Subjects: p14ARF -- Prostate cancer -- Androgen receptor -- Apoptosis -- E2F; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.03.030
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Prostate cancer (PCa) is characterized by a unique dependence on optimal androgen receptor (AR) activity where physiological androgen concentrations induce proliferation but castrate and supraphysiological levels suppress growth. This feature has been exploited in bipolar androgen therapy (BAT) for castrate resistant malignancies. Here, we investigated the role of the tumor suppressor protein p14ARF in maintaining optimal AR activity and the function of the AR itself in regulating p14ARF levels. We used a tumor tissue array of differing stages and grades to define the relationships between these components and identified a strong positive correlation between p14ARF and AR expression. Mechanistic studies utilizing CWR22 xenograft and cell culture models revealed that a decrease in AR reduced p14ARF expression and deregulated E2F factors, which are linked to p14ARF and AR regulation. Chromatin immunoprecipitation studies identified AR binding sites upstream of p14ARF. p14ARF depletion enhanced AR-dependent PSA and TMPRSS2 transcription, hence p14ARF constrains AR activity. However, p14ARF depletion ultimately results in apoptosis. In PCa cells, AR co-ops p14ARF as part of a feedback mechanism to ensure optimal AR activity for maximal prostate cancer cell survival and proliferation. Highlights: There is a correlation between AR and p14ARF expression in prostate cancers. The AR directly regulates p14ARF transcription to constrain its own activity. P14ARF deletion ultimately results in apoptosis of prostate cancer cells.