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PGC1? promotes tumor growth by inducing gene expression programs supporting lipogenesis.

ABSTRACT: Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPAR? coactivator 1? (PGC1?) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1? expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1? is associated with cancer cell proliferation. Therefore, the role of PGC1? in cancer and especially carcinogenesis is unclear. Using Pgc1?(-/-) and Pgc1?(+/+) mice, we show that loss of PGC1? protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1?(-/-) mice as compared with Pgc1?(+/+) mice. Xenograft studies using gain and loss of PGC1? expression showed that PGC1? also promotes tumor growth. Interestingly, while PGC1? induced oxidative phosphorylation and tricarboxylic acid cycle gene expression, we also observed an increase in the expression of two genes required for de novo fatty acid synthesis, ACC and FASN. In addition, SLC25A1 and ACLY, which are required for the conversion of glucose into acetyl-CoA for fatty acid synthesis, were also increased by PGC1?, thus linking the oxidative and lipogenic functions of PGC1?. Indeed, using stable (13)C isotope tracer analysis, we show that PGC1? increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1?. In conclusion, these studies show for the first time that loss of PGC1? protects against carcinogenesis and that PGC1? coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth.

SUBMITTER: Bhalla K

PROVIDER: S-EPMC3282487 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.

Bhalla Kavita K Hwang Bor Jang BJ Dewi Ruby E RE Ou Lihui L Twaddel William W Fang Hong-Bin HB Vafai Scott B SB Vazquez Francesca F Puigserver Pere P Boros Laszlo L Girnun Geoffrey D GD

Cancer research 20110913 21

Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1α is associated with cancer cell proliferation. Therefore, the ...[more]

PMID: 21914785

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Project description:BackgroundHepatitis B virus (HBV) transcription and replication are essentially restricted to hepatocytes. Based on the HBV enhancer and promoter complex that links hepatic glucose metabolism to its transcription and replication, HBV adopts a regulatory system that is unique to the hepatic gluconeogenic genes. CRTC2, the CREB-regulated transcription coactivator 2, is a critical switch modulating the gluconeogenic program in response to both hormonal and intracellular signals. However, the relationship between CRTC2 and HBV transcription and replication remains unclear.MethodsTo analyze the influence of CRTC2 on HBV transcription and replication, CRTC2 expression construct or siRNA was cotransfected with plasmids containing enhancer II/core promoter complex-controlled luciferase or 1.3× wtHBV genome in Huh-7 cells. Luciferase activity, HBV core protein expression, HBV transcripts, and DNA replication intermediates were measured by luciferase assays, western blots, real-time polymerase chain reaction (PCR), and Southern blots, respectively. Forskolin (FSK) or phosphorylation-defective CRTC2 mutants were further utilized to elucidate the potential mechanism. siRNA against peroxisome proliferator-activated receptor-? coactivator 1? (PGC1?) was also used to examine the mediator involved in CRTC2-regulated HBV biosynthesis in Huh-7 cells.ResultsCRTC2 overexpression increased HBV transcription and replication in Huh-7 cells, including levels of core protein expression, mRNA, and DNA replication intermediates. Correspondingly, CRTC2 knock down by siRNA reduced HBV biosynthesis. FSK treatment strongly enhanced the effect of CRTC2 through triggering the dephosphorylation and nuclear entry of CRTC2. The phosphorylation-defective mutant (S171A/S275A) of CRTC2 localized in the nucleus and was constitutively active, which dramatically promoted HBV transcription and replication similar to FSK-treated wild-type CRTC2. Knock down of PGC1?, whose expression was induced by CRTC2, greatly compromised the enhancing effect of CRTC2 on HBV transcription and replication.ConclusionsOur results clearly indicate that non-phosphorylated CRTC2 strongly enhances HBV biosynthesis through inducing PGC1? expression. Further study of the mechanisms will elucidate the importance of metabolic signals on HBV transcription and replication, and offer insight into potential targets for developing anti-HBV agents.

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PGC1? promotes tumor growth by inducing gene expression programs supporting lipogenesis.

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PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.

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