MYB proto-oncogene like 2 promotes hepatocellular carcinoma growth and glycolysis via binding to the Optic atrophy 3 promoter and activating its expression

Optic atrophy 3 (OPA3) is an integral protein of the mitochondrial outer membrane. The current study explored the expression of OPA3 in hepatocellular carcinoma (HCC), its association with the prognosis and its involvement in HCC cell proliferation and aerobic glycolysis. In addition, the transcription factors that activate its expression were screened and validated. Gene expression data in normal liver and liver cancer were acquired from the Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (TCGA-LIHC). Chromatin immunoprecipitation-seq data (GSM1010876) in Cistrome Data Browser was used for searching transcriptional factors binding to the OPA3 promoter. HCC cell lines HLF and JHH2 were used for in-vitro and in-vivo studies. Results showed that OPA3 is significantly upregulated in HCC and associated with unfavorable prognosis. OPA3 knockdown impaired HCC cell growth in vitro and in vivo. Besides, it decreased glucose uptake, lactate production, intracellular ATP levels, and extracellular acidification rate (ECAR) of HLF and JHH2 cells. MYB Proto-Oncogene Like 2 (MYBL2) can bind to the promoter of OPA3 and enhance its transcription. MYBL2 knockdown decreased aerobic glycolysis in HCC cells. OPA3 overexpression reversed these alterations. In conclusion, this study revealed a novel MYBL2-OPA3 axis that enhances HCC cell proliferation and aerobic glycolysis.