Abstract
Glucose is a critical nutrient for cell proliferation. However, the molecular pathways that regulate glucose metabolism are still elusive. We discovered that co-activator-associated arginine methyltransferase 1 (CARM1) suppresses glucose metabolism toward serine biosynthesis. By tracing the 13C-labeled glucose, we found that Carm1 knockout mouse embryonic fibroblasts exhibit significantly increased de novo serine synthesis than WT cells. This is caused, at least in part, by the reduced pyruvate kinase (PK) activity in these cells. The M2 isoform of PK (PKM2) is arginine-methylated by CARM1, and methylation enhances its activity. Mechanistically, CARM1 methylates PKM2 at arginines 445 and 447, which enhances PKM2 tetramer formation. Consequently, Carm1 knockout cells exhibit significant survival advantages over WT cells when extracellular serine is limited, likely due to their enhanced de novo serine synthesis capacity. Altogether, we identified CARM1 as an important regulator of glucose metabolism and serine synthesis.
Highlights
Glucose is a critical nutrient for cell proliferation
Adding to the compelling evidence defining the role of co-activator-associated arginine methyltransferase 1 (CARM1) in transcription regulation and mRNA splicing, our study revealed a novel aspect of CARM1 function in regulating cell metabolism, which may shed light on the role of this important enzyme in development and disease
Studies of CARM1 function in human cancer revealed that overexpression of CARM1 inhibits the proliferation and induces differentiation of breast cancer MCF7 cells [47] and that CARM1-overexpressing breast cancer cells are more sensitive to chemotherapy druginduced cell death [46]
Summary
Whereas CARM1 has been increasingly recognized as an important regulator of lipid and amino acid metabolism [19, 39], its role in glucose metabolism remains largely unexplored. To test this model and determine the importance of the methylation-mediated interactions in enhancing PKM2 activity, we increased the distance between Arg-447 and Leu-392 or Phe-421 by replacing leucine or phenylalanine with alanine Both L392A and F421A mutants of PKM2 exhibited baseline levels of PK activity comparable with that of the WT enzyme (Fig. S4D) and were able to be methylated by CARM1 (data not shown). Depletion in Carm knockout MEFs (Fig. 6C), supporting the argument that reduced PK activity is the primary mechanism driving this resistance This result further confirmed that reduced PK activity in Carm knockout cells channels glucose flux to de novo serine synthesis. CARM1 knockout MCF7 cells exhibited reduced PK activity and were resistant to depletion of extracellular serine (Fig. S5), suggesting that the mechanism identified in MEFs applies to some cancer cell lines
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