NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling

Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdo...

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Veröffentlicht in:	Nature cell biology Jg. 24; H. 9; S. 1422 - 1432
Hauptverfasser:	Verma, Sachin, Crawford, David, Khateb, Ali, Feng, Yongmei, Sergienko, Eduard, Pathria, Gaurav, Ma, Chen-Ting, Olson, Steven H., Scott, David, Murad, Rabi, Ruppin, Eytan, Jackson, Michael, Ronai, Ze’ev A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.09.2022 Nature Publishing Group
Schlagworte:	13 13/1 13/106 13/109 13/2 13/31 13/44 13/89 13/95 14 38 38/39 45 45/41 631/67/1813/1634 631/80/82/23 631/80/86/2366 64 64/60 692/699/67/2327 82 96 Activating transcription factor 3 Addictions Amino Acid Metabolism, Inborn Errors - genetics Amino Acid Metabolism, Inborn Errors - metabolism Apoptosis Biomedical and Life Sciences Brain Diseases, Metabolic - genetics Brain Diseases, Metabolic - metabolism Brain Diseases, Metabolic - pathology Cancer Research Catabolism Cell Biology Cell death Depletion Developmental Biology DNA Glutaryl-CoA dehydrogenase Glutaryl-CoA Dehydrogenase - genetics Glutaryl-CoA Dehydrogenase - metabolism Humans Inactivation Ketoglutarate Dehydrogenase Complex Life Sciences Lysine Melanoma Melanoma - genetics Mitochondria Mitochondrial Proteins Mortality NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Protein turnover Proteins Signal transduction Signaling Stem Cells Tumors
ISSN:	1465-7392, 1476-4679, 1476-4679
Online-Zugang:	Volltext
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Zusammenfassung:	Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma. Verma et al. demonstrate that GCDH depletion in melanoma cells induces NRF2 glutarylation, upregulates ATF4 and ATF3 signalling and promotes cell death, thereby suppressing tumour growth.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Genentech, San Francisco, CA, USA
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-022-00985-x