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BCDIN3D RNA methyltransferase stimulates Aldolase C expression and glycolysis through let-7 microRNA in breast cancer cells

Oncogene volume 40, pages 2395–2406 (2021)Cite this article

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Abstract

Type II diabetes (T2D) and specific cancers share many risk factors, however, the molecular mechanisms underlying these connections are often not well-understood. BCDIN3D is an RNA modifying enzyme that methylates specific precursor microRNAs and tRNAHis. In addition to breast cancer, BCDIN3D may also be linked to metabolism, as its gene locus is associated with obesity and T2D. In order to uncover metabolic pathways regulated by BCDIN3D in cancer, we performed an unbiased analysis of the metabolome, transcriptome, and proteome of breast cancer cells depleted for BCDIN3D. Intersection of these analyses showed that BCDIN3D-depleted cells have increased levels of Fructose 1,6 Bisphosphate (F1,6-BP), the last six-carbon glycolytic intermediate accompanied by reduced glycolytic capacity. We further show that elevated F1,6-BP is due to downregulation of Aldolase C (ALDOC), an enzyme that cleaves F1,6-BP mainly in the brain, but whose high expression/amplification is associated with poor prognosis in breast cancer. BCDIN3D regulates ALDOC through a non-canonical mechanism involving the crucial let-7 microRNA family and its target site on the 3′UTR of ALDOC. Overall, our results reveal an important connection between BCDIN3D, let-7 and glycolysis that may be relevant to breast cancer, obesity, and T2D.

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Fig. 1: BCDIN3D depletion reduces tumor formation in vivo.
Fig. 2: BCDIN3D knock-down profoundly affects gene expression in breast cancer cells.
Fig. 3: BCDIN3D regulates the levels of F1,6-BP and glycolysis through ALDOC.
Fig. 4: BCDIN3D stimulates ALDOC through a non-canonical mechanism involving let-7 microRNAs.

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Acknowledgements

BX was supported by NIH (R01-GM127802, DOD-CDMRP-BCRP (W81XWH-16-1-0352), Welch Foundation (F1859), STORM Therapeutics, and start-up funds. CVDB was partly supported by CPRIT (RR160093). This study made use of the MD Anderson Science Park facilities supported by CPRIT Core Facility Support Grants RP120348 and RP170002 and P30 CA16672 DHHS/NCI Cancer Center Support Grant (CCSG).

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  1. These authors contributed equally: Calder W. Reinsborough, Hélène Ipas, Nathan S. Abell

Authors and Affiliations

  1. Department of Molecular Biosciences, LiveStrong Cancer Institute at Dell Medical School, University of Texas at Austin, 2500 Speedway, Austin, TX, 78712, USA

    Calder W. Reinsborough, Hélène Ipas, Nathan S. Abell, Ellen B. Gouws, J. Paige Williams, Marvin Mercado & Blerta Xhemalçe

  2. Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5324, USA

    Nathan S. Abell

  3. Division of Pharmacology & Toxicology, College of Pharmacy, and Department of Oncology, University of Texas at Austin, Dell Medical School, Austin, TX, 78723, USA

    Carla Van Den Berg

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Reinsborough, C.W., Ipas, H., Abell, N.S. et al. BCDIN3D RNA methyltransferase stimulates Aldolase C expression and glycolysis through let-7 microRNA in breast cancer cells. Oncogene 40, 2395–2406 (2021). https://doi.org/10.1038/s41388-021-01702-y

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