The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics
William Giblin, … , Costas A. Lyssiotis, David B. Lombard
William Giblin, … , Costas A. Lyssiotis, David B. Lombard
Published May 4, 2021
Citation Information: J Clin Invest. 2021;131(12):e138926. https://doi.org/10.1172/JCI138926.
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Research Article Cell biology Metabolism

The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics

Abstract

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that regulates metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we showed that SIRT5 was required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 was required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf Pten–driven melanoma model. Via metabolite and transcriptomic analyses, we found that SIRT5 was required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably included MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a druggable genotype-independent addiction in melanoma.

Authors

William Giblin, Lauren Bringman-Rodenbarger, Angela H. Guo, Surinder Kumar, Alexander C. Monovich, Ahmed M. Mostafa, Mary E. Skinner, Michelle Azar, Ahmed S.A. Mady, Carolina H. Chung, Namrata Kadambi, Keith-Allen Melong, Ho-Joon Lee, Li Zhang, Peter Sajjakulnukit, Sophie Trefely, Erika L. Varner, Sowmya Iyer, Min Wang, James S. Wilmott, H. Peter Soyer, Richard A. Sturm, Antonia L. Pritchard, Aleodor A. Andea, Richard A. Scolyer, Mitchell S. Stark, David A. Scott, Douglas R. Fullen, Marcus W. Bosenberg, Sriram Chandrasekaran, Zaneta Nikolovska-Coleska, Monique E. Verhaegen, Nathaniel W. Snyder, Miguel N. Rivera, Andrei L. Osterman, Costas A. Lyssiotis, David B. Lombard

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Figure 1

Increased SIRT5 copy number in human melanoma.

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Increased SIRT5 copy number in human melanoma. (A) Gain of extra SIRT5 c...
(A) Gain of extra SIRT5 copies in melanoma. BRAF, NRAS, PTEN, MITF, NF1 and other sirtuins are shown for comparison (n = 287; data from TCGA, Provisional, analyzed on cBioPortal). ND, not determined. Percentage of samples with any genomic alteration (Any) or amplification or gain (Amp/Gain) is indicated. Graphed are any alterations queried for the indicated gene. Copy number gain indicates a low-level gain of a single additional copy, and amplification refers to high-level amplification (multiple extra copies). Results from the query (GENE: MUT AMP HOMDEL GAIN HETLOSS) in cBioPortal were analyzed and plotted. (B) Kaplan-Meier analysis of overall survival in melanoma patients with or without copy number gain or amplification of SIRT5. Overall survival was analyzed using the query, “SIRT5: AMP GAIN.” (C) SIRT5 (6p23) and centromere 6p (Cen6p) amplification (amp) or coamplification (Co-amp) in melanoma, as assayed by FISH staining (n = 32). (D) Sirtuin gene copy number (CN) in human melanoma samples, as assayed by high density SNP array (n = 139). (E) SIRT5 mRNA expression levels in melanoma correlate with Clark’s level (P = 0.0044, linear regression; P = 0.037, 1-way ANOVA). (F) SIRT5 protein levels are increased in melanoma relative to benign melanocytic lesions (P = 0.0333, χ2; n = 14 nevi, n = 87 melanoma). See also Supplemental Figure 1 and Supplemental Table 1.