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

Abstract

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)alpha/gamma 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 PPARalpha/gamma 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 PPARalpha/gamma ligands in prostate cancer cell lines. Pursuing PPARalpha/gamma signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARalpha/gamma activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARalpha/gamma 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 PPARalpha/gamma 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-PPARalpha/gamma and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARalpha/gamma selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance.

VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription

“…Members of this superfamily are expressed in virtually all cell types and are highly integrated functionally. [2][3][4][5] These receptors represent some of the most successful examples of targeted therapies [6][7][8][9] and, more widely, in human disease they represent the target for approximately 15% of all drugs (reviewed in 10,11 ). Of the family of 48 NRs, at least 30 are expressed in the prostate 2 and many are well established in the etiology of prostate cancer (CaP), for example, the androgen receptor (AR) (reviewed in 12 ), VDR (reviewed in 9 ), and the peroxisome proliferator-activated receptors (PPARs) (reviewed in 6 ).…”

“…20,21 Similar distortions to PPAR signaling occurs. 2,3,22,23 These de-regulated responses appear particularly amenable to targeted restoration with epigenetic therapies.…”

Aberrant Nuclear Repressor Coreceptor 1 Localization in Human Retinoblastoma

“…Abnormal levels and/or subcellular distribution of NCoR1 are involved in oncogenesis. While the levels of NCoR1 are upregulated in prostate cancer, its cytoplasmic shuttling is seen in colorectal cancer [18,19,20]. In addition, levels of NCoR1 also predict response to tamoxifen therapy in breast cancer [12,21].…”

The multifaceted factor peroxisome proliferator-activated receptor γ (PPARγ) in metabolism, immunity, and cancer

“…Adipocyte-specific knockout PPARc mice display more susceptibility toward DMBA-induced breast cancer than wild-type mice . In prostate cancer, upregulated NcoR1, a PPARc negative cofactor, demonstrates negative effects on tumorigenesis (Battaglia et al 2010).…”