The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics

William Giblin, Lauren Bringman-Rodenbarger, Angela H Guo, Surinder Kumar, Alexander C Monovich, Ahmed M Mostafa, Mary E Skinner, Michelle Azar, Ahmed Sa 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 WilmottH 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 Osterman, Costas A Lyssiotis, David B Lombard

Research output: Contribution to journalArticlepeer-review

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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 achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is 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 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

Original languageEnglish
Article numbere138926
Pages (from-to)1-18
Number of pages18
JournalJournal of Clinical Investigation
Volume131
Issue number12
Early online date4 May 2021
DOIs
Publication statusPublished - 15 Jun 2021

Keywords

  • Cell Biology
  • Metabolism

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