BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer

Abstract

Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC, are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibiton, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growthin vitroandin vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC- independent and GDH1-dependendent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.