The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics.

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. 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. RNA-seq was performed on A2058, A375, and SKMEL-2 cell lines infected with either control or SIRT5 shRNA (KD1 or KD2), for a total of 27 samples on the Illumina HiSeq4000 with 50nt paired-end sequencing. Alignment was conducted using STAR v.2.7.3a against Gencode (GRCh38 Release 34 primary assembly), counted using featureCounts, and differential expression was determined using DESeq2 v.1.28.1. A more detailed description is provided in the manuscript. Please note that one of the raw files associated with the 'A375 Non-targetting Control Rep 2' sample is truncated (70414_1_1.fq.gz).