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PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

ABSTRACT: Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1?) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1? expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1? in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1? are also essential for functional motility of cancer cells and metastasis.

SUBMITTER: LeBleu VS

PROVIDER: S-EPMC4369153 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

LeBleu Valerie S VS O'Connell Joyce T JT Gonzalez Herrera Karina N KN Wikman Harriet H Pantel Klaus K Haigis Marcia C MC de Carvalho Fernanda Machado FM Damascena Aline A Domingos Chinen Ludmilla Thome LT Rocha Rafael M RM Asara John M JM Kalluri Raghu R

Nature cell biology 20140921 10

Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, ...[more]

PMID: 25241037

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Project description:During neural development, epigenetic modulation of chromatin acetylation is part of a dynamic, sequential and critical process to steer the fate of multipotent neural progenitors toward a specific lineage. Pan-HDAC inhibitors (HDCis) trigger neuronal differentiation by generating an "acetylation" signature and promoting the expression of neurogenic bHLH transcription factors. Our studies and others have revealed a link between neuronal differentiation and increase of mitochondrial mass. However, the neuronal regulation of mitochondrial biogenesis has remained largely unexplored. Here, we show that the HDACi, sodium butyrate (NaBt), promotes mitochondrial biogenesis via the NRF-1/Tfam axis in embryonic hippocampal progenitor cells and neuroprogenitor-like PC12-NeuroD6 cells, thereby enhancing their neuronal differentiation competency. Increased mitochondrial DNA replication by several pan-HDACis indicates a common mechanism by which they regulate mitochondrial biogenesis. NaBt also induces coordinates mitochondrial ultrastructural changes and enhanced OXPHOS metabolism, thereby increasing key mitochondrial bioenergetics parameters in neural progenitor cells. NaBt also endows the neuronal cells with increased mitochondrial spare capacity to confer resistance to oxidative stress associated with neuronal differentiation. We demonstrate that mitochondrial biogenesis is under HDAC-mediated epigenetic regulation, the timing of which is consistent with its integrative role during neuronal differentiation. Thus, our findings add a new facet to our mechanistic understanding of how pan-HDACis induce differentiation of neuronal progenitor cells. Our results reveal the concept that epigenetic modulation of the mitochondrial pool prior to neurotrophic signaling dictates the efficiency of initiation of neuronal differentiation during the transition from progenitor to differentiating neuronal cells. The histone acetyltransferase CREB-binding protein plays a key role in regulating the mitochondrial biomass. By ChIP-seq analysis, we show that NaBt confers an H3K27ac epigenetic signature in several interconnected nodes of nuclear genes vital for neuronal differentiation and mitochondrial reprogramming. Collectively, our study reports a novel developmental epigenetic layer that couples mitochondrial biogenesis to neuronal differentiation.

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PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

Publications

PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.

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