Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer

Audet-Walsh, Étienne; Yee, Tracey; McGuirk, Shawn; Vernier, Mathieu; Ouellet, Carlo; St-Pierre, Julie; Giguère, Vincent

doi:10.1158/0008-5472.can-16-1204

Cited by 69 publications

(65 citation statements)

References 46 publications

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“…Although AR is recruited to the regulatory regions of many of the genes involved in these metabolic processes, numerous androgen-sensitive genes are not direct AR transcriptional targets (Audet-Walsh et al 2017) but were identified in our study as direct targets of mTOR ( Fig. 4; Supplemental Fig.…”

Section: Discussionmentioning

confidence: 68%

“…The central role played by AR in the development and progression of PCa is well appreciated, including its role in reprogramming mitochondrial metabolism (Tennakoon et al 2014;Audet-Walsh et al 2017). Although AR is recruited to the regulatory regions of many of the genes involved in these metabolic processes, numerous androgen-sensitive genes are not direct AR transcriptional targets (Audet-Walsh et al 2017) but were identified in our study as direct targets of mTOR ( Fig.…”

Section: Discussionmentioning

confidence: 70%

“…S5D). Reorganization of cellular nutrient utilization in PCa cells by AR activation is achieved in large part by altering the activity of mitochondria (Tennakoon et al 2014;Audet-Walsh et al 2017). In support of this notion, PCa cells treated with R1881 were found to be more sensitive to treatment with etomoxir, an inhibitor of fatty acid oxidation (FAO) (Fig.…”

Section: A Functional Nuclear Mtor-ar Axis Is Required For the Metabomentioning

confidence: 69%

“…Through the process of malignant transformation, citrate and zinc accumulation ceases, which is thought to be the consequence of restored mitochondrial function and increased lipid synthesis from citrate production (Costello et al 2005;Costello and Franklin 2017). In PCa, androgens and their receptor have been shown to fuel cell metabolism by rewiring nutrients and altering citrate metabolism, notably by inducing mitochondrial activity, de novo lipogenesis, and aerobic glycolysis (Massie et al 2011;Tennakoon et al 2014;Audet-Walsh et al 2017). mTOR is another critical regulator of metabolism and cancer cell growth (Menon and Manning 2008;Laplante and Sabatini 2013).…”

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confidence: 99%

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Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 70%

Section: A Functional Nuclear Mtor-ar Axis Is Required For the Metabomentioning

confidence: 69%

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confidence: 99%

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Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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“…Loss of ESRRG has previously been implicated in other malignancies including prostate cancer where it impacts proliferation (52,53). ESRRG has also been implicated in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

Nam

Chandrashekar

Kundu

et al. 2019

Molecular Cancer Research

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The Cancer Genome Atlas (TCGA) and other large-scale genomic data pipelines have been integral to the current understanding of the molecular events underlying renal cell carcinoma (RCC). These data networks have focused mostly on primary RCC, which often demonstrates indolent behavior. However, metastatic disease is the major cause of mortality associated with RCC and data sets examining metastatic tumors are sparse. Therefore, a more comprehensive analysis of gene expression and DNA methylome profiling of metastatic RCC in addition to primary RCC and normal kidney was performed. Integrative analysis of the methylome and transcriptome identified over 30 RCC-specific genes whose mRNA expression inversely correlated with promoter methylation, including several known targets of hypoxia inducible factors. Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation including hexokinase 2, aldolase C, stearoyl-CoA desaturase, and estrogen-related receptor-γ (ESRRG), which has a known role in the regulation of nuclear-encoded mitochondrial metabolism genes. Several gene expression changes could portend prognosis in the TCGA cohort. Mechanistically, ESRRG loss occurs via DNA methylation and histone repressive silencing mediated by the polycomb repressor complex 2. Restoration of ESRRG in RCC lines suppresses migratory and invasive phenotypes independently of its canonical role in mitochondrial metabolism. Collectively, these data provide significant insight into the biology of aggressive RCC and demonstrate a novel role for DNA methylation in the promotion of HIF signaling and invasive phenotypes in renal cancer.

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Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic–mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer

et al. 2023

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The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient‐derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography–mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry‐based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic–mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.

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Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer

Cited by 69 publications

References 46 publications

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic–mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer

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