HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

De Huang; Tingting Li; Xinghua Li; Long Zhang; Linchong Sun; Xiaoping He; Xiuying Zhong; Dongya Jia; Libing Song; Gregg L. Semenza; Ping Gao; Huafeng Zhang

doi:10.1016/j.celrep.2014.08.028

HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

De Huang, Tingting Li, Xinghua Li, Long Zhang, Linchong Sun, Xiaoping He, Xiuying Zhong, Dongya Jia, Libing Song, Gregg L. Semenza, Ping Gao, Huafeng Zhang

School of Medicine

Research output: Contribution to journal › Article › peer-review

152 Scopus citations

Abstract

Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1α also inhibits fatty acid β-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1β-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth invivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.

Original language	English (US)
Pages (from-to)	1930-1942
Number of pages	13
Journal	Cell Reports
Volume	8
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2014.08.028
State	Published - Sep 25 2014

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2014.08.028

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title = "HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression",

abstract = "Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1α also inhibits fatty acid β-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1β-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth invivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.",

author = "De Huang and Tingting Li and Xinghua Li and Long Zhang and Linchong Sun and Xiaoping He and Xiuying Zhong and Dongya Jia and Libing Song and Semenza, {Gregg L.} and Ping Gao and Huafeng Zhang",

note = "Funding Information: Our work is supported in part by National Basic Key Research Program of China (2014CB910601, 2014CB910604, and 2012CB910104), Chinese Academy of Sciences (XDA01010404), National Nature Science Foundation of China (31171358, 31371429, 81372148, and 31071257). H.Z. is supported by Chinese Government “1000 Youth Talent Program.” Publisher Copyright: {\textcopyright} 2014 The Authors.",

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doi = "10.1016/j.celrep.2014.08.028",

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T1 - HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

AU - Huang, De

AU - Li, Tingting

AU - Li, Xinghua

AU - Zhang, Long

AU - Sun, Linchong

AU - He, Xiaoping

AU - Zhong, Xiuying

AU - Jia, Dongya

AU - Song, Libing

AU - Semenza, Gregg L.

AU - Gao, Ping

AU - Zhang, Huafeng

N1 - Funding Information: Our work is supported in part by National Basic Key Research Program of China (2014CB910601, 2014CB910604, and 2012CB910104), Chinese Academy of Sciences (XDA01010404), National Nature Science Foundation of China (31171358, 31371429, 81372148, and 31071257). H.Z. is supported by Chinese Government “1000 Youth Talent Program.” Publisher Copyright: © 2014 The Authors.

PY - 2014/9/25

Y1 - 2014/9/25

N2 - Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1α also inhibits fatty acid β-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1β-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth invivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.

AB - Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1α also inhibits fatty acid β-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1β-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth invivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.

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HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression

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