SUMOylated hnRNPM suppresses PFKFB3 phosphorylation to regulate glycolysis and tumorigenesis

Heterogeneous nuclear ribonucleoprotein M (hnRNPM), a splicing regulatory factor with a majority of studies focused on its RNA-binding properties and effects on splicing outcome, is implicated in the progression of various kinds of human cancers, but its mechanisms remain largely enigmatic. Applying the global SUMOylated proteomic screening in colorectal cancer cells, herein we find that hnRNPM is SUMOylated at lysine 17 and Sentrin-specific protease 1 (SENP1) is essential for its de-SUMOylation. Although hnRNPM SUMOylation does not affect its known pre-mRNA splicing-related effects, more intriguingly, it remarkably influences lactate production. Mechanistically, SUMOylated hnRNPM interacts with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to affect its localization and inhibit its phosphorylation, thus suppressing glycolysis. Accordingly, SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice. Also, a negative correlation between hnRNPM SUMOylation and SENP1 expression or phosphorylated PFKFB3 levels can be found in CRC patient samples. These findings not only enhance our understanding of the multifaceted roles of hnRNPM in cancer biology but also open new avenues for the development of targeted therapies aimed at modulating hnRNPM SUMOylation.