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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Vydáno v:Nature cell biology Ročník 24; číslo 9; s. 1422 - 1432
Hlavní autoři: 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.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 01.09.2022
Nature Publishing Group
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ISSN:1465-7392, 1476-4679, 1476-4679
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Abstract 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.
AbstractList 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.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.
Tumor 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 programs 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 programs. Mechanistically, GCDH KD 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 ftumor growth. Correspondingly, reduced GCDH expression correlated with improved survival of melanoma patients. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signaling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.
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.
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.
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.
Author Ma, Chen-Ting
Olson, Steven H.
Feng, Yongmei
Scott, David
Murad, Rabi
Khateb, Ali
Crawford, David
Verma, Sachin
Ruppin, Eytan
Ronai, Ze’ev A.
Jackson, Michael
Sergienko, Eduard
Pathria, Gaurav
AuthorAffiliation 2 Cancer Data Science Lab (CDSL), National Cancer Institute, National Institute of Health, Bethesda, MD 20892
3 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
1 Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36050469$$D View this record in MEDLINE/PubMed
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Current address: Genentech, San Francisco, CA, USA
ORCID 0000-0002-3859-0400
OpenAccessLink https://www.ncbi.nlm.nih.gov/pmc/articles/9977532
PMID 36050469
PQID 2715007146
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crossref_primary_10_1038_s41556_022_00985_x
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PublicationCentury 2000
PublicationDate 20220900
2022-09-01
2022-09-00
20220901
PublicationDateYYYYMMDD 2022-09-01
PublicationDate_xml – month: 9
  year: 2022
  text: 20220900
PublicationDecade 2020
PublicationPlace London
PublicationPlace_xml – name: London
– name: England
PublicationTitle Nature cell biology
PublicationTitleAbbrev Nat Cell Biol
PublicationTitleAlternate Nat Cell Biol
PublicationYear 2022
Publisher Nature Publishing Group UK
Nature Publishing Group
Publisher_xml – name: Nature Publishing Group UK
– name: Nature Publishing Group
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Snippet Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the...
Tumor dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the...
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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
Title NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling
URI https://link.springer.com/article/10.1038/s41556-022-00985-x
https://www.ncbi.nlm.nih.gov/pubmed/36050469
https://www.proquest.com/docview/2715007146
https://www.proquest.com/docview/2709741090
https://pubmed.ncbi.nlm.nih.gov/PMC9977532
Volume 24
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