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 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.
Highlights
Clear cell renal cell carcinoma is histologically defined by its lipid and glycogen-rich cytoplasmic deposits
To begin to dissect the mechanism of lipid deposition in Clear cell renal cell carcinoma (ccRCC) cells, we evaluated the ability of three ccRCC cell lines (RCC4, RCC10, and 786-O) to make lipid droplets
We found that all three cell lines developed lipid droplets as revealed by Oil Red O staining (Fig. 1a, upper panels) at 2–8 days after reaching confluence
Summary
Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. 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. While great strides have been made in identifying the genetic alterations driving ccRCC development[2], the significance of, and molecular mechanisms leading to, the clear cell phenotype are incompletely appreciated. A recent analysis of programs altered in ccRCC compared to normal kidneys identified an adipogenic gene signature, and led to studies that demonstrated that ccRCC cells can undergo trans-differentiation when exposed to established adipogenic differentiation protocols[8], suggesting some mechanistic insight into the lipid deposition phenotype. Abnormal cancer metabolism leads to changes in decisions regarding FA fates, including the altered balance in ccRCC toward excessive storage in the form of lipids. FA metabolism via ER-bound enzymes leads to production of diacylglycerol, which can be stored as triglycerides in the lipid droplet; while FA transport into the mitochondrion via CPT1 a RCC4
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