MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma

• Published in: Oncogene Vol. 38; no. 34; pp. 6211 - 6225
• Main Authors: Green, Nathanael H., Galvan, Daniel L., Badal, Shawn S., Chang, Benny H., LeBleu, Valerie S., Long, Jianyin, Jonasch, Eric, Danesh, Farhad R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2019; Nature Publishing Group
• Subjects: 13/106; 13/89; 38/91; 631/67/589/1588/1351; 631/80/304; Aminohydrolases - physiology; Animals; Apoptosis; Carbohydrate Metabolism - genetics; Carbon; Carcinoma, Renal cell; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cellular Reprogramming - genetics; Development and progression; Gene Expression Regulation, Neoplastic; Genetic aspects; Glycolysis; Glycolysis - genetics; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Metabolism; Methylation; Methylenetetrahydrofolate Dehydrogenase (NADP) - physiology; Methyltransferases - metabolism; Mice; Mice, Nude; Mitochondria; mRNA; Multifunctional Enzymes - physiology; N6-methyladenosine; Oncology; Renal cell carcinoma; RNA Processing, Post-Transcriptional - genetics; RNA sequencing; Translation; Tumor cells; Tumorigenesis; Xenografts
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-019-0869-4

One-carbon metabolism plays a central role in a broad array of metabolic processes required for the survival and growth of tumor cells. However, the molecular basis of how one-carbon metabolism may influence RNA methylation and tumorigenesis remains largely unknown. Here we show MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, contributes to the progression of renal cell carcinoma (RCC) via a novel epitranscriptomic mechanism that involves HIF-2α. We found that expression of MTHFD2 was significantly elevated in human RCC tissues, and MTHFD2 knockdown strongly reduced xenograft tumor growth. Mechanistically, using an unbiased methylated RNA immunoprecipitation sequencing (meRIP-Seq) approach, we found that MTHFD2 plays a critical role in controlling global N
6
-methyladenosine (m
6
A) methylation levels, including the m
6
A methylation of HIF-2α mRNA, which results in enhanced translation of HIF-2α. Enhanced HIF-2α translation, in turn, promotes the aerobic glycolysis, linking one-carbon metabolism to HIF-2α-dependent metabolic reprogramming through RNA methylation. Our findings also suggest that MTHFD2 and HIF-2α form a positive feedforward loop in RCC, promoting metabolic reprograming and tumor growth. Taken together, our results suggest that MTHFD2 links RNA methylation status to the metabolic state of tumor cells in RCC.