MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

Aberrant alternative splicing (AS) is implicated in cancer metabolic reprogramming that supplies cancer cells with energy and substrates for biosynthesis. Therefore, the elucidation of the mechanism underlying aberrant AS in cancer cells is important for developing specific and effective therapy. We demonstrated that MTR4, a RNA helicase important for RNA quality surveillance, is frequently overexpressed in hepatocellular carcinoma (HCC) and is correlated with increased glycolysis and poor prognosis of HCC patients. MTR4 is required for tumorigenesis of HCC cells by promoting glycolysis and expression of glycolytic genes. MTR4 binds to specific motifs of pre-mRNAs, including those of the key glycolytic genes, and regulates their AS by recruiting PTBP1. We discovered that MTR4 is a direct transcriptional target of c-Myc, suggesting that MTR4 mediates the metabolic function of c-Myc in HCC. These findings reveal mechanisms driving cancer-specific AS profile and present MTR4 as a specific therapeutic target for treating HCC. Overall design: RNA-sequencing of MTR4 knockdown PLC/PRF5 and wild Control PLC/PRF5.