Hyperglycemia modulates epigenetic expression of Neuregulin1 through Notch-Rbpj axis

Abstract

Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Neuregulin1 (NRG1) encodes a ligand for HER3, which is a member of epidermal growth factor family of receptor tyrosine kinases (EGFR). Among the various isoforms of NRG1, NRG1-β1 is overexpressed in the cancer cells by hyperglycemic stimuli via putative distal enhancer activities. However, the specific mechanisms involved in hyperglycemic memory in NRG1 gene is poorly understood. In this study, we investigated how NRG1-β1 is epigenetically regulated under hyperglycemic condition by utilizing enhancer-bait pulldown assay to identify the enhanceosome protein complex. Among the putative candidates, Rbpj was selected as a transcriptional regulator of NRG1-β1, which plays a central role in Notch signaling. Notch signaling was activated in hyperglycemic cancer cells, and DAPT, a notch inhibitor, treatment reduced the Nrg1-β1 expression. We confirmed that Nrg1 enhancer regions which are modulated by hyperglycemia in cancer cells are active motif as enhancer marks such as H3k4me1 and H3k27ac were significantly elevated by hyperglycemia. Our results will provide the fundamental knowledge how diabetes contribute to breast cancer progression, which may be through hyperglycemic memory effects on Nrg1 oncogene.