Emerging Roles for SIRT5 in Metabolism and Cancer

Bringman-Rodenbarger, Lauren; Guo, Angela H.; Lyssiotis, Costas A.; Lombard, David B.

doi:10.1089/ars.2017.7264

Cited by 107 publications

(84 citation statements)

References 117 publications

(271 reference statements)

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“…Figure 8G). These results, along with those already in the literature (6), suggest that SIRT5 may play potent oncogenic roles across many diverse tumor types, seemingly engaging a variety of different cellular…”

Section: Discussionsupporting

confidence: 79%

“…Among these proteins, Sirtuin 5 (SIRT5) has remained a somewhat enigmatic and poorly characterized sirtuin. SIRT5 is atypical, in that it lacks robust deacetylase activity, and primarily functions to remove succinyl, malonyl, and glutaryl modifications from lysines on its target proteins, in mitochondria and throughout the cell, thereby regulating multiple metabolic pathways (6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple sirtuins are now linked to neoplasia, as tumor suppressors and/or oncogenes, in a context-specific manner (21). The functions of SIRT5 in cancer are incompletely understood, and a subject of active investigation (6). For example, SIRT5 promotes chemoresistance in nonsmall cell lung carcinoma cells by enhancing NRF2 activity and expression of its targets involved in cellular antioxidant defense (22).…”

Section: Introductionmentioning

confidence: 99%

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The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Giblin

Bringman-Rodenbarger

Kumar

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Giblin

Bringman-Rodenbarger

Kumar

et al. 2020

Preprint

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“…The conflicting evidence based on a number of studies suggests that all three mitochondrial sirtuins can act either as a tumor suppressor or as a tumor promoter, likely depending on the cellular and/or tissue context. This has been discussed further in several recent reviews (68)(69)(70), and persists in the context of skin cancer as well.…”

Section: Role Of Mitochondrial Sirtuins In Skin Cancersmentioning

confidence: 88%

Mitochondrial Sirtuins in Skin and Skin Cancers

Ndiaye

Singh

et al. 2020

Photochem & Photobiology

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Mammalian sirtuins (SIRTs 1‐7) are a family of NAD+‐dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs ‐3, ‐4 and ‐5 are located in the mitochondria and have been implicated in caloric restriction, oxidative stress, aging and various human diseases. Emerging evidence has found dysregulation of mitochondrial sirtuins in multiple dermatological conditions, including responses to ultraviolet radiation (UVR), suggesting their importance in maintaining skin health. In this review, we discuss the roles and implications of mitochondrial sirtuins in cutaneous cellular processes, and their emerging potential as a target for the management of skin diseases, including skin cancer. Among mitochondrial sirtuins, SIRT3 is the most studied and linked to multiple skin conditions and diseases (keratinocyte differentiation, wound healing, chronological aging, UVR and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). SIRT4 has been connected to keratinocyte differentiation, chronological aging, UVR response, alopecia, BCC and SCC. Further, SIRT5 has been associated with keratinocyte differentiation, melanoma, BCC and SCC. Overall, while there is compelling evidence for the involvement of mitochondrial sirtuins in skin, additional detailed studies are needed to understand their exact roles in skin and skin cancers.

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“…This regulation has been suggested to affect various proteins involved in cellular metabolism and other processes . Moreover, Sirt5 has been implicated as a regulator of cancer cell metabolism . However, there have been conflicting results in previous studies aimed at identifying a role for Sirt5 in cancer cells, as Sirt5 appears to act as both a tumor promoter and suppressor depending on the type of cancer .…”

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confidence: 99%

Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma development and growth in vivo

Moon

Zhu

White

2019

Experimental Dermatology

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Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for BrafV600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (TyrCreERT2/+; BrafLSL‐V600E/+; Ptenflox/flox) to Sirt5−/− knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5−/− mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.

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Emerging Roles for SIRT5 in Metabolism and Cancer

Cited by 107 publications

References 117 publications

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Mitochondrial Sirtuins in Skin and Skin Cancers

Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma development and growth in vivo

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Emerging Roles for SIRT5 in Metabolism and Cancer

Cited by 107 publications

References 117 publications

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Mitochondrial Sirtuins in Skin and Skin Cancers

Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma development and growth in vivo

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Resources

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Sirt5 is dispensable for Braf^V600E‐mediated cutaneous melanoma development and growth in vivo