Melanoma Addiction to GCDH is Mediated by NRF2

We identify melanoma addiction to the mitochondrial protein Glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown promoted ATF4-ATF3 signaling and cell death programs in melanoma cells, an activity blocked by knockdown of the upstream lysine catabolism enzyme DHTKD1. Correspondingly, reduced GCDH expression correlated with improved survival of melanoma patients. We show that a key mediator of GCDH-dependent melanoma cell death programs is the transcription factor NRF2, which induces ATF4, ATF3, DDIT3, and CHAC1 transcription, linking lysine catabolism with apoptotic signaling Overall design: Gene expression comparison of siGCDH and siControl in A375 (melanoma), SK_Hep1 (liver cancer), and SKBR3(breast cancer) using RNA-seq.