# Role of SIRT3 in melanoma development and progression

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2022 · —

## Abstract

Melanoma, one of the deadliest cancer of skin, arises from melanocytic cells that are responsible for
melanin production. Recent advances in the understanding of melanoma biology has led to the development of
targeted therapies with promise. For example, BRAF inhibitors vemurafenib and dabrafenib achieved
significant improvement over chemotherapy and were approved for metastatic melanomas with BRAF-
mutations. More recently, the combination of dabrafenib with MEK inhibitor trametinib demonstrated improved
progression-free survival, compared to monotherapy, and has received approval from the US FDA. However,
even with the combination treatment, most of the patients develop acquired resistance, thereby failing to
achieve lasting tumor regression. Therefore, novel target-based approaches are needed for the management
of melanomas. The mammalian sirtuins constitute a family of seven known members (SIRT1 – SIRT7) with
NAD+-dependent protein deacetylase and/or ADP-ribosyltransferase activities]. In addition, they are also
known to regulate post-translational acyl modifications. SIRTs play critical roles in important cellular processes,
and are shown to be involved in the pathogenesis of a variety of diseases, including cancer. The role of SIRTs
in cancer is extremely complex and they appears to have dichotomous functions depending on cell contexts.
Among known SIRTs, SIRT3 is a mitochondrial sirtuin, which coordinates global shift in mitochondrial activity
by deacetylating proteins involved in diverse mitochondrial functions. It also plays important roles in the
regulation of a variety of cellular processes, including transcription, insulin secretion, and apoptosis. The fact
that SIRT3 can regulate several cellular processes which are critical in cancer cell proliferation, makes it a
potential therapeutic target for cancer management. While the research on the role of SIRT3 in cancer is still in
its infancy, studies have suggested its tumor suppressor as well as tumor promoter roles. However, the role of
SIRT3 in melanoma is not known. In our preliminary data, we have found that SIRT3 is overexpressed in
melanoma and its inhibition results in a significant anti-proliferative response in melanoma cells. Further, we
have also found that 4'-bromo-resveratrol (4BR), a new small molecule inhibitor of SIRT3, imparts anti-
proliferative effects in human melanoma cells. Thus, based on available literature and our preliminary data, we
propose to test the hypothesis that SIRT3 plays a critical role in melanoma progression via modulating
p53 signaling, Ku70-Bax interaction and/or cellular metabolic homeostasis. The following specific aims
are proposed: 1) o define the role of SIRT3 in melanoma development and progression, employing a tissue
microarray (TMA) created from retrospective melanoma tissues from veteran patients, and an in vitro cell
transformation model; 2) to define the involvement of p53 signaling, Ku70-Bax interaction, cellular metabolic
homeostasis...

## Key facts

- **NIH application ID:** 10683063
- **Project number:** 5I01CX001441-06
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Nihal Ahmad
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683063

## Citation

> US National Institutes of Health, RePORTER application 10683063, Role of SIRT3 in melanoma development and progression (5I01CX001441-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10683063. Licensed CC0.

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