MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma.

Abstract:

: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 N6-methyladenosine (m6A) methylation levels, including the m6A 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.

journal_name

Oncogene

journal_title

Oncogene

authors

Green NH,Galvan DL,Badal SS,Chang BH,LeBleu VS,Long J,Jonasch E,Danesh FR

doi

10.1038/s41388-019-0869-4

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

6211-6225

issue

34

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-019-0869-4

journal_volume

38

pub_type

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