Expression of HMGB2 indicates worse survival of patients and is required for the maintenance of Warburg effect in pancreatic cancer

Abstract

High mobility group proteins (HMGs) are the second most abundant chromatin proteins and exert global genomic functions in the establishment of active or inactive chromatin domains. Through interaction with nucleosomes, transcription factors, nucleosome-remodeling machines and histones, the HMGs family proteins contribute to the fine tuning of transcription in response to rapid environmental changes. Mammalian high mobility group Bs (HMGBs) are characterized by two tandem HMG box domains followed by a long acidic tail. Recent studies demonstrated that high expression of HMGBs has been found in many cancers, such as prostate, kidney, ovarian, and gastric cancers. However, their roles in pancreatic cancer have seldom been reported. In this study, we assessed the diagnostic and prognostic values of HMGBs proteins, including HMGB1, HMGB2, and HMGB3, in pancreatic cancer from the Cancer Genome Atlas (TCGA) dataset. Our results demonstrated that HMGB2 predicted poor prognosis in pancreatic cancer. In vitro studies demonstrated that silencing HMGB2 inhibited cell proliferation and viability. Mechanistically, our results demonstrated that silencing HMGB2 decreased hypoxia inducible factor 1α (HIF1α) protein level and inhibited HIF1α-mediated glycolysis process. Further analysis indicated that HIF1α-targeted glycolytic genes, including GLUT1, HK2, and LDHA, are all prognostic factors and positively correlated with HMGB2 expression. Taken together, we discovered new prognostic and predictive markers for pancreatic cancer, and shed light on the novel function of HMGB2 in glycolytic control in cancer.