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Title: HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism
Author: Du, Weinan
Zhang, Luchang
Brett-Morris, Adina
Aguila, Brittany
Kerner, Janos
Hoppel, Charles L.
Puchowicz, Michelle
Serra i Cucurull, Dolors
Herrero Rodríguez, Laura
Rini, Brian I.
Campbell, Steven
Welford, Scott M.
Keywords: Càncer de ronyó
Àcids grassos
Renal cancer
Fatty acids
Issue Date: 24-Nov-2017
Publisher: Nature Publishing Group
Abstract: Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxiainducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis.
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It is part of: Nature Communications, 2017, vol. 8, num. 1, p. 1769
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ISSN: 2041-1723
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

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