Exon Skipping of Ste20-Like Kinase Enhances Glycolysis and Tumor Progression by Activating Enolase 1 mediated Phosphoenolpyruvate Production
Dysregulated RNA splicing is activated in tumors; however, the metabolic landscape and consequent implications of this process remain largely unexplored. In this study, we identified exon skipping in Ste20-like kinase (SLK), resulting in a variant isoform of SLK (SLKv), which promotes glycolysis in tumor cells. Mechanistically, SLKv enhances the activity of enolase 1 (ENO1) by binding and phosphorylating the ENO1 serine 2 residue. This modification increases the efficiency of ENO1 in catalyzing the production of phosphoenolpyruvate (PEP). Notably, the accumulation of PEP further accelerates glycolysis by binding to and activating the glycolytic enzyme hexokinase 2 (HK2), phosphofructokinase muscle (PFKM), and phosphoglycerate mutase 1 (PGAM1). Meanwhile, transforming growth factor ß (TGFß) promotes exon skipping of SLK by upregulating the splicing factor KH RNA binding domain containing, signal transduction associated 1 (KHDRBS1). The application of antisense oligonucleotides (ASO) that target SLKv hinders glycolysis and tumorigenesis. These findings establish SLKv as a critical promoter of glycolysis and present a novel metabolic target for cancer therapy. Overall design: RNA-seq profiling of wildtype MHCC-97H, MDA-MB-231 and HCT-116 treatment with DMSO/ H3B-8800 in 24hrs