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.
View: Text | PDF
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

×

Figure 6

Transcriptomic analysis reveals MITF dependency on SIRT5 expression.

Options: View larger image (or click on image) Download as PowerPoint
Transcriptomic analysis reveals MITF dependency on SIRT5 expression. Gen...
Genes (A) upregulated or (B) downregulated upon SIRT5 KD. Only genes significantly (P < 0.05) altered in both KDs in each cell line, as indicated, were scored. (C) Expression levels of DEGs (qadj < 0.05) in response to SIRT5 KD were correlated with SIRT5 gene expression using Spearman’s rank correlation coefficient in 443 sequenced human skin cutaneous melanoma (SKCM) samples, identifying DEGs with significant clinical correlation with SIRT5 expression (q < 0.01). Labeled genes represent oncogenes or extremely correlated genes most significantly altered by SIRT5 KD (q < 0.0001, log2 fold change > 2). (D) Expression of SIRT5, MITF, and the MITF target, PPARGC1A, are positively correlated in melanoma clinical samples (P < 0.0001, data from TCGA, analyzed on cBioPortal; see Figure 1A).