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BCDIN3D RNA methyltransferase stimulates Aldolase C expression and glycolysis through let-7 microRNA in breast cancer
Calder W Reinsborough1, Hélène Ipas1, Nathan S Abell1,2
1Department of Molecular Biosciences, LiveStrong Cancer Institute at Dell Medical School, University of Texas at Austin, 2500 Speedway, Austin, TX, 78712, USA.
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.
Insights
BCDIN3D enzyme impacts cancer metabolism by altering glycolysis. It regulates Aldolase C (ALDOC) via the let-7 microRNA, affecting Fructose 1,6 Bisphosphate levels, which has implications for breast cancer, obesity, and Type II diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Type II diabetes (T2D) and cancers share risk factors, with unclear molecular links.
- BCDIN3D, an RNA modifying enzyme, is implicated in breast cancer and metabolic disorders like obesity and T2D.
- Understanding BCDIN3D's role in cancer metabolism is crucial for identifying therapeutic targets.
Purpose of the Study:
- To investigate metabolic pathways regulated by BCDIN3D in cancer.
- To uncover the molecular mechanisms connecting BCDIN3D, microRNAs, and cancer metabolism.
- To explore the potential relevance of these findings to T2D and obesity.
Main Methods:
- Unbiased metabolomic, transcriptomic, and proteomic analysis of BCDIN3D-depleted breast cancer cells.
- Quantification of Fructose 1,6 Bisphosphate (F1,6-BP) levels and assessment of glycolytic capacity.
- Investigation of Aldolase C (ALDOC) regulation by BCDIN3D, including the role of the let-7 microRNA family.
Main Results:
- BCDIN3D depletion led to increased F1,6-BP and reduced glycolytic capacity.
- Elevated F1,6-BP was attributed to ALDOC downregulation.
- BCDIN3D was shown to regulate ALDOC via a non-canonical let-7 microRNA mechanism targeting ALDOC's 3'UTR.
Conclusions:
- BCDIN3D plays a significant role in regulating glycolysis in breast cancer cells.
- A novel regulatory axis involving BCDIN3D, let-7 microRNA, and ALDOC impacts F1,6-BP levels.
- These findings suggest a molecular link between BCDIN3D, glycolysis, and diseases including breast cancer, obesity, and T2D.
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