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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics
William Giblin1,2, Lauren Bringman-Rodenbarger1, Angela H Guo1
1Department of Pathology and.
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.
Insights
Sirtuin 5 (SIRT5) is crucial for melanoma cell survival and proliferation, regardless of genetic mutations. Targeting SIRT5 could offer a new treatment strategy for various melanoma types.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cutaneous melanoma is a lethal skin cancer with limited durable remission rates for advanced cases.
- Current therapies like immune checkpoint inhibitors and targeted treatments benefit only about half of advanced melanoma patients.
- Sirtuin 5 (SIRT5), a protein deacetylase, regulates cellular metabolism and biological functions.
Purpose of the Study:
- To investigate the role of SIRT5 in the proliferation and survival of cutaneous and uveal melanoma cells.
- To determine if SIRT5 is essential for melanoma tumor formation in preclinical models.
- To elucidate the molecular mechanisms by which SIRT5 influences melanoma gene expression.
Main Methods:
- Assessed SIRT5's requirement for melanoma cell proliferation and survival across various genotypes.
- Utilized melanoma xenograft and autochthonous mouse models to evaluate tumor formation.
- Performed metabolite and transcriptomic analyses to understand SIRT5's impact on histone modifications and gene expression.
Main Results:
- SIRT5 is essential for the proliferation and survival of all tested cutaneous and uveal melanoma genotypes.
- SIRT5 deficiency impaired melanoma xenograft tumor formation and development in a Braf Pten-driven mouse model.
- SIRT5 maintains histone acetylation and methylation levels, crucial for regulating genes like MITF and c-MYC.
Conclusions:
- SIRT5 is a critical factor for melanoma cell viability and tumorigenesis, independent of specific genetic mutations.
- SIRT5 regulates key oncogenes, including MITF and c-MYC, through epigenetic modifications.
- SIRT5 presents a potential druggable target for melanoma treatment across different subtypes.
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