Elevated NCOR1 disrupts PPARα/γ signaling in prostate cancer and forms a targetable epigenetic lesion

• Published in: Carcinogenesis (New York) 2010-09, Vol.31 (9), p.1650-1660
• Main Authors: Battaglia, Sebastiano, Maguire, Orla, Thorne, James L., Hornung, Laura B., Doig, Craig L., Liu, Song, Sucheston, Lara E., Bianchi, Anna, Khanim, Farhat L., Gommersall, Lyndon M., Coulter, Henry S.O., Rakha, Serena, Giddings, Ian, O'Neill, Laura P., Cooper, Colin S., McCabe, Christopher J., Bunce, Christopher M., Campbell, Moray J.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carcinogenesis; Carcinogenesis, carcinogens and anticarcinogens; Gynecology. Andrology. Obstetrics; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgq086

The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)α/γ may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes. Expression patterns were dependent on phases of the cell cycle and associated with repressed basal gene expression of vitamin D receptor and PPARα/γ target genes, for example CDKN1A [encodes p21(waf1/cip1)]. Elevated nuclear corepressor 1 (NCOR1) and nuclear corepressor 2/silencing mediator of retinoic acid and thyroid hormone receptor protein levels were detected in prostate cancer cell lines compared with non-malignant counterparts. Knockdown of the corepressor NCOR1 significantly elevated basal expression of a cohort of target genes, including CDKN1A. Both chemical [histone deacetylases inhibitor (HDACi)] and NCOR1 knockdown targeting enhanced anti-proliferative sensitivity toward PPARα/γ ligands in prostate cancer cell lines. Pursuing PPARα/γ signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARα/γ activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARα/γ gene targets centered on, for example cell cycle control, including CDKN1A and TGFBRAP1. Quantitative real time polymerase chain reaction validation and chromatin immunoprecipitation assays both confirmed that elevated NCOR1 disrupted the ability of PPARα/γ to regulate key target genes (CDKN1A and TGFBRAP1). Interrogation of these relationships in prostate cancer samples using principal component and partial correlation analyses established significant interdependent relationships between NCOR1–PPARα/γ and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARα/γ selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance.