Cell reports · 2025
IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation.
СтатьяПоддержка правительства СШАПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Sharma Gunjan, Gutierrez Martin, Jones Anthony E, Kapoor Shruti, Jaiswal Amit Kumar, Neeb Zachary T, Rios Amy, Dorairaj Poornima, Thaxton Michelle L, Lin Tasha L, Tran Tiffany M, Kabbani Lyna E S, Ritter Alexander J, Scherer Georgia M, Sorrentino Jacob P, Stiles Linsey, Hoeve Johanna Ten, Damoiseaux Robert D, Garg Neil K, Divakaruni Ajit S, Sanford Jeremy R, Rao Dinesh S
Аннотация
Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein and a non-canonical reader of N6-methyladenosine (m6A) mRNA modifications, is known to be critical for leukemogenesis. To understand how the oncogenic function of IGF2BP3 impacts metabolism, we performed metabolic profiling and observed changes in glycolytic flux and one-carbon metabolism, including the biosynthesis of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. Using enhanced crosslinking immunoprecipitation (eCLIP) and polyribosome profiling, we found that IGF2BP3 promotes translation of the regulatory subunit of the methionine adenosyltransferase complex (MAT2B), which is involved in SAM production. Remarkably, IGF2BP3 promotes and alters the level and pattern of m6A modifications on mRNA. Taken together, these data suggest the intriguing hypothesis that IGF2BP3 rewrites the epitranscriptome in leukemia cells. Furthermore, this work highlights an interconnection between oncogenic metabolism and RNA modifications, suggesting that pervasive gene expression changes necessary for oncogenesis may be perpetuated by post-transcriptional gene regulation.