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Updated: Feb 28, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Mechanisms of the Antiproliferative Effects of SIRT6 Inhibition in Melanoma: A Multi-Omics Analysis
Karla B Anaya Aldrete1, Durdana Muntaqua1, Liz M Garcia-Peterson1
1Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Background/Objectives:
Melanoma is one of the deadliest types of skin cancer due to its ability to metastasize if not treated early. While targeted- and immune- therapies have significantly improved melanoma treatment outcomes, acquired drug resistance even with combined therapeutics remain prevalent. SIRT6 is a nuclear histone deacetylase that regulates DNA repair, metabolism, and chromatin remodeling. It is overexpressed in melanoma and its inhibition in melanoma is known to have anti-proliferative response, and alterations in pathways related to cell cycle, senescence, and metastasis.
Methods:
To deepen our understanding of the role of SIRT6 in melanoma, in this study we utilized RNA sequencing, proteomics, and Ingenuity Pathway Analysis on genetically modified human melanoma cells to determine the downstream mechanism of SIRT6 in melanoma.
Results:
SIRT6 knock down (KD) in A375 and G361 melanoma cells, with CRISPR/Cas9 or shRNA techniques, resulted in a significant decrease in proliferation and clonogenic survival of the cells. SIRT6 KD caused an altered expression of multiple genes associated with cell proliferation, mitotic regulation, invasion, cell death/senescence, and immunomodulation, including AURKB, ANLN, MYC, FOXM1, RABL6, E2F2, TP53, RBL1, OSM, TNF, IL1B, IL6, and IFNG. Comparative analysis at both transcription and translation levels revealed coordinated downregulation of proliferation, invasion, and migration and upregulation of targets related to cell death, apoptosis, and necrosis. Multi-omics analysis also predicted downregulation of signaling networks associated with MAP3K20, MYC, MKNK, and HMGCR.
Conclusions:
Given its involvement in tumorigenesis, this study underlines the importance of SIRT6 in melanoma and provides support to its potential as a novel therapeutic target for melanoma.
Insights
SIRT6 (silent mating type information regulation 2 homolog 1) is overexpressed in melanoma and drives cancer progression. Inhibiting SIRT6 significantly reduces melanoma cell proliferation and invasion, highlighting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma is a deadly skin cancer with high metastatic potential.
- Acquired drug resistance limits current targeted and immune therapies.
- SIRT6, a nuclear histone deacetylase, is overexpressed in melanoma and linked to proliferation, cell cycle, senescence, and metastasis.
Purpose of the Study:
- To elucidate the downstream mechanisms of SIRT6 in melanoma.
- To investigate the role of SIRT6 in melanoma cell proliferation, survival, and metastasis.
Main Methods:
- Utilized RNA sequencing, proteomics, and Ingenuity Pathway Analysis.
- Employed CRISPR/Cas9 and shRNA for SIRT6 knockdown (KD) in human melanoma cells (A375, G361).
- Performed comparative analysis at transcriptional and translational levels.
Main Results:
- SIRT6 KD significantly decreased melanoma cell proliferation and clonogenic survival.
- Altered expression of genes involved in cell cycle, invasion, and immunomodulation observed.
- Downregulation of proliferation/invasion pathways and upregulation of cell death pathways confirmed via multi-omics.
Conclusions:
- SIRT6 plays a critical role in melanoma tumorigenesis.
- SIRT6 inhibition demonstrates anti-melanoma effects.
- SIRT6 is a promising novel therapeutic target for melanoma treatment.
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