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Androgen-dependent repression of estrogen-related receptor γ expression mediates metabolic reprogramming in prostate cancer

ABSTRACT: Androgens are central to prostate cancer (PCa) development and targeting this pathway is currently the main therapeutic axis in the clinic, but the mechanism by which androgen signaling contributes to the oncometabolic state of PCa cells remains to be fully elucidated. The intersection of gene expression, binding-events and motif finding analyses following androgen exposure identified a metabolic gene signature associated with the action of estrogen-related receptors (ERRs). Unexpectedly, we show that ERRγ acts as a negative regulator of mitochondrial respiration in the context of PCa, and that AR-dependent direct repression of ERRγ promotes the reactivation of a functional TCA cycle. This metabolic state, which parallels the loss of ERRγ expression, was observed in both androgen-dependent and castration-resistant PCa and was associated with cell proliferation. Interrogation of several clinical studies revealed a strong inverse relationship between ERRγ expression and the severity of the disease. Our study uncovers a novel mechanism by which AR-dependent repression of ERRγ contributes to the reprogramming of PCa cell metabolism to favor mitochondrial activity and cell proliferation. We used microarrays to investigate the transcriptional regulation of metabolic genes by 72h treatment with R1881, a synthetic androgens, with or without repression of the estrogen-related receptor gamma, in LNCaP prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86781 | GEO | 2016/12/06

SECONDARY ACCESSION(S): PRJNA342490

REPOSITORIES: GEO

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Project description:Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (~25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (~23%), five events involved transcripts derived from known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of the alternative TSC2 mRNA isoform was directly regulated by androgens. Furthermore, by chromatin immunoprecipitation, we observed recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa. Total 8 samples were analysed. 4 control (LNCaP cells grown in RPMI-1640 media with charcoal-stripped 10% FBS devoid of steroids) and 4 treatment (LNCaP cells grown in media devoid of steroid, and subsequently treated with 10nM R1881 synthetic androgen analogue for 24 hours).

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Androgen-dependent repression of estrogen-related receptor γ expression mediates metabolic reprogramming in prostate cancer

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