AACR Grantees Uncover Novel Roles of SIRT5 in Cutaneous and Uveal Melanoma
More than half of melanomas contain extra copies of the SIRT5 gene (which encodes sirtuin 5/SIRT5). Unlike other sirtuins, sirtuin 5 does not have robust deacetylase activity. 2017 AACR-Bayer Innovation and Discovery Grant recipient David B. Lombard, MD, PhD led a research group that demonstrated that SIRT5 is required for melanoma cell growth and survival. SIRT5 significantly contributes to histone acetylation levels in cutaneous and uveal melanoma cells. Key SIRT5-dependent genes include the melanoma lineage-specific survival oncogene MITF and the c-MYC proto-oncogene.
Dr. Lombard received an AACR-Bayer Innovation and Discovery Grant in 2017, allowing him to determine the role of SIRT5, particularly in uveal melanoma.
In this recent paper in Journal of Clinical Investigation, he and his colleagues report how SIRT5 loss led to apoptotic cell death, not only in uveal melanoma cells, but also in cutaneous melanoma cells in vitro. In vivo studies confirmed that SIRT5 loss-of function inhibited melanoma tumor growth. Transcriptomic analyses on SITR5-depleted cells, and TCGA data analyses on melanoma samples, revealed a correlation between the expression of SIRT5 and melanocyte inducing transcription factor (MITF). MITF has been shown to be critical for melanogenesis.1 Knocking down SIRT5 downregulated the expression not only of MITF, but also of MITF’s canonical targets: genes involved in metabolism (PPARGC1A) and cell survival (BCL2), among others.
The sirtuin family of proteins regulate metabolism. The authors analyzed their transcriptomic data using the Recon1 human network model to predict the metabolic pathways that SIRT5 regulates in melanoma. Two of the pathways that were identified involve the enzymes ATP-citrate lyase (ACLY) and mitochondrial methylenetetrahydrofolate dehydrogenase. ACLY has been previously shown to regulate histone acetylation under certain conditions2. Mitochondrial methylenetetrahydrofolate dehydrogenase is involved in folate and one-carbon metabolism. One-carbon metabolism provides the building blocks for other cellular pathways, including DNA and histone methylation3.
The authors confirmed that SIRT depletion resulted in reduction in total histone acetylation, and in H3K4 and H3K4 trimethylation. In particular, reduction of acetylation of H3K9 in the promoter regions of MITF and c-MYC was observed through CUT&RUN-qPCR studies. This suggests that SIRT5 activates the transcription of these genes, at least in part, by promoting histone acetylation. Cells that survived despite SIRT5 depletion showed baseline histone acetylation and H3K4 and H3K4 trimethylation levels, suggesting that SIRT5’s impact on cell viability is due at least in part to its regulatory role in histone modification.
Given the role of SIRT5 in melanoma cell survival and the benign consequences of Sirt5 knockout (at least in mice), Dr. Lombard and his colleagues propose that SIRT5 may be a good therapeutic target. This is particularly good news for metastatic uveal melanoma patients for whom there are currently no effective treatment options.
These findings on the importance of SIRT5 in melanoma come from a big group of scientists that include a number of recipients of AACR grants. Like Dr. Lombard, one of the authors, Dr. Zaneta Nikolovska-Coleska, received an AACR-Bayer Innovation and Discovery Grant (2019). She has been exploring the therapeutic potential of dual Mcl-1/Mfl-1 inhibition in melanoma . Another grantee, Dr. Costas Lyssiotis, has received multiple AACR grants (the most recent one is a 2017 AACR NextGen Grant for Transformative Cancer Research) that have helped bolster his work in metabolism.
1 Hartman and Czyz. 2015. J Invest Dermatol 135:352-8.
2 Wellen et al. 2009. Science 324:1076-80
3 Serefidou et al., 2019. Front Genet. 10:764