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Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function

Sachin Verma, David Crawford, Ali Khateb, Yongmei Feng, Eduard Sergienko, Gaurav Pathria, Chen-Ting Ma, Steven H Olson, David Scott, Rabi Murad, Eytan Ruppin, Michael Jackson, Ze’ev A Ronai
doi: https://doi.org/10.1101/2021.10.22.465495
Sachin Verma
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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David Crawford
2Cancer Data Science Lab (CDSL), National Cancer Institute, National Institute of Health, Bethesda, MD 20892
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Ali Khateb
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Yongmei Feng
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Eduard Sergienko
3Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Gaurav Pathria
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Chen-Ting Ma
3Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Steven H Olson
3Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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David Scott
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Rabi Murad
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Eytan Ruppin
2Cancer Data Science Lab (CDSL), National Cancer Institute, National Institute of Health, Bethesda, MD 20892
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Michael Jackson
3Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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Ze’ev A Ronai
1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037
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  • For correspondence: zeev@ronailab.net
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Abstract

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.

Competing Interest Statement

ZAR is founder and scientific adviser for Pangea Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 23, 2021.
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Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function
Sachin Verma, David Crawford, Ali Khateb, Yongmei Feng, Eduard Sergienko, Gaurav Pathria, Chen-Ting Ma, Steven H Olson, David Scott, Rabi Murad, Eytan Ruppin, Michael Jackson, Ze’ev A Ronai
bioRxiv 2021.10.22.465495; doi: https://doi.org/10.1101/2021.10.22.465495
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Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function
Sachin Verma, David Crawford, Ali Khateb, Yongmei Feng, Eduard Sergienko, Gaurav Pathria, Chen-Ting Ma, Steven H Olson, David Scott, Rabi Murad, Eytan Ruppin, Michael Jackson, Ze’ev A Ronai
bioRxiv 2021.10.22.465495; doi: https://doi.org/10.1101/2021.10.22.465495

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