Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression

Abstract

Owing to the enhanced glycolytic rate, cancer cells generate lactate copiously, which in turn, promotes lactylation of histone. Even though histone lactylation has been explored to alter the expression of few genes, the role of this epigenetic modification in regulating the expression of oncogenes is largely unchartered. In this study, using breast cancer cell lines their mutants (which exhibit lactate-deficient metabolome), we have identified that intracellular lactate promotes histone lactylation-dependent c-Myc upregulation. Furthermore, we report that the c-Myc upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing in breast cancer cells. Our findings provide novel mechanistic insights into the role assayed by aerobic glycolysis in orchestrating alternative splicing that collectively drive breast tumorigenesis. Moreover, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.