Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function

Tumor dependency on specific metabolic signals has guided numerous therapeutic approaches. Here we identify melanoma addiction to the mitochondrial protein Glutaryl-CoA dehydrogenase (GCDH), a component in lysine metabolism which controls protein glutarylation. GCDH knockdown promoted apoptotic Unfolded Protein Response signaling and cell death 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. A key mediator of GCDH-dependent melanoma cell death programs is the transcription factor NRF2, which induces ATF3, CHOP, and CHAC1 transcription linking lysine catabolism with the UPR signaling. NRF2 glutarylation upon GCDH KD increased its stability and DNA binding activity, which coincided with increased transcriptional activity, promoting apoptotic UPR signaling and tumor suppression. In vivo, genetic GCDH inhibition effectively inhibited melanoma tumor growth. Overall, these findings demonstrate an addiction of melanoma cells to GCDH, which by controlling NRF2 glutarylation limits apoptotic UPR signaling. Inhibiting the GCDH pathway could represent a novel therapeutic modality to treat melanoma.