Genome-wide chromatin profiles of ZNF395 [RNA-seq]

Hypoxia signaling induced by VHL deficiency fuels growth but also poses immense metabolic stress to clear cell renal cell carcinomas (ccRCCs). Tumor cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor alpha (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. We now show that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. ZNF395 is activated by a HIF2α-modulated super-enhancer but plays non-redundant functions from HIF2α. Specifically, ZNF395 facilitates the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2 (IDH2). Functionally, ZNF395 depletion results in reduced TCA intermediates and their derivatives, including amino acids, glutathione and pyrimidine nucleotides. In addition, ZNF395 depletion diminishes mitochondrial respiration; restoration of complex I function rescues the effects of ZNF395 depletion. Our study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.