TY - JOUR
T1 - HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism
AU - Du, Weinan
AU - Zhang, Luchang
AU - Brett-Morris, Adina
AU - Aguila, Brittany
AU - Kerner, Janos
AU - Hoppel, Charles L.
AU - Puchowicz, Michelle
AU - Serra, Dolors
AU - Herrero, Laura
AU - Rini, Brian I.
AU - Campbell, Steven
AU - Welford, Scott M.
N1 - Funding Information:
This work was supported by the following grants: American Cancer Society 121762-RSG-12-097-01-CCG, NIH R21 CA178157-01A1, AACR 14-60-36-WELF, and CTSC 4UL1TR000439. The Cytometry and Microscopy Core Facility of the Case Comprehensive Cancer Center, which is supported by P30CA43703, was used in this study. We also thank Thomas F. Peterson, Jr, for his generosity.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 hypoxia-inducible 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.
AB - 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 hypoxia-inducible 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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U2 - 10.1038/s41467-017-01965-8
DO - 10.1038/s41467-017-01965-8
M3 - Article
C2 - 29176561
AN - SCOPUS:85035057913
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1769
ER -