Dataset Information

ERR? Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1?-Elevated Melanomas.

ABSTRACT: The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1? function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1?-independent tumor cells becomes endowed with an augmented metastatic phenotype. To find PGC1?-dependent components that would not affect metastasis in melanomas, an unbiased proteomic analyses was performed and uncovered the orphan nuclear receptor ERR?, which supports PGC1?'s control of mitochondrial energetic metabolism, but does not affect the antioxidant nor antimetastatic regulatory roles. Specifically, genetic or pharmacologic inhibition of ERR? reduces the inherent bioenergetic capacity and decreases melanoma cell growth, but without altering the invasive characteristics. Thus, within this particularly aggressive subset of melanomas, which is characterized by heighted expression of PGC1?, ERR? specifically mediates prosurvival functions and represents a tangible therapeutic target.Implications: ERR?, a druggable protein, mediates the bioenergetic effects in melanomas defined by high PGC1? expression, suggesting a rational means for therapeutic targeting of this particularly aggressive melanoma subtype. Mol Cancer Res; 15(10); 1366-75. ©2017 AACR.

SUBMITTER: Luo C

PROVIDER: S-EPMC5954239 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α-Elevated Melanomas.

Luo Chi C Balsa Eduardo E Thomas Ajith A Hatting Maximilian M Jedrychowski Mark M Gygi Steven P SP Widlund Hans R HR Puigserver Pere P

Molecular cancer research : MCR 20170608 10

The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1α function to sustain their mi ...[more]

PMID: 28596418

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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?), the cofactor and activator of oestrogen-related receptor ? (ERR?). PGC1? knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERR? agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1?-ERR? axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.

Dataset Information

ERR? Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1?-Elevated Melanomas.

Publications

ERRα Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1α-Elevated Melanomas.

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