IGF2BP3 redirects glycolytic flux to promote one-carbon metabolism and RNA methylation
Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein and a non-canonical reader of N6-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A 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.
Authors
- Anthony E. Jones (ORCID: https://orcid.org/0000-0003-2058-6021)
- Ajit S. Divakaruni (ORCID: https://orcid.org/0000-0002-2528-9651)
- S. S. Kapoor (ORCID: https://orcid.org/0000-0003-4216-8488)
- Zachary T. Neeb (ORCID: https://orcid.org/0000-0001-8930-3574)
- Martin Gutierrez (ORCID: https://orcid.org/0000-0003-3156-3159)
- Tasha Lin (ORCID: https://orcid.org/0000-0003-4281-4152)
- Johanna ten Hoeve (ORCID: https://orcid.org/0000-0003-0226-749X)
- Alexander J. Ritter (ORCID: https://orcid.org/0000-0002-1998-7357)
- Gunjan Sharma (ORCID: https://orcid.org/0000-0003-3110-9239)
- Robert D. Damoiseaux (ORCID: https://orcid.org/0000-0002-7611-7534)
- Jeremy R. Sanford (ORCID: https://orcid.org/0000-0002-1131-1627)
- Dinesh S. Rao (ORCID: https://orcid.org/0000-0002-0794-9337)
- Jacob P. Sorrentino (ORCID: https://orcid.org/0000-0001-5071-5379)
- Georgia Scherer (ORCID: https://orcid.org/0000-0003-4924-9723)
- Amit Kumar Jaiswal (ORCID: https://orcid.org/0000-0002-6566-3580)
- Tiffany Tran (ORCID: https://orcid.org/0000-0003-2163-3520)
- Linsey Stiles (ORCID: https://orcid.org/0000-0002-1514-458X)
- Neil K. Garg (ORCID: https://orcid.org/0000-0002-7793-2629)
- Michelle L. Thaxton
- Lyna E.S. Kabbani
- Amy Rios
- Poornima Dorairaj
Institutions
- University of California, Los Angeles (US)
- University of California, Santa Cruz (US)
- Los Angeles Medical Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-27
- DOI
- https://doi.org/10.1016/j.celrep.2025.116330
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61