# Mechanisms of the Antiproliferative Effects of SIRT6 Inhibition in Melanoma: A Multi-Omics Analysis

## TL;DR

This study explores how blocking a protein called SIRT6 can slow the growth of melanoma cancer cells and suggests it could be a new target for treatment.

## Contribution

The study reveals new mechanisms by which SIRT6 inhibition suppresses melanoma growth through multi-omics analysis.

## Key findings

- Reducing SIRT6 in melanoma cells significantly decreased their proliferation and survival.
- SIRT6 inhibition altered genes and proteins linked to cancer growth and activated cell death pathways.
- Multi-omics analysis showed downregulation of key signaling networks like MYC and HMGCR.

## Abstract

Melanoma is an aggressive skin cancer that can spread quickly if not treated early. While new treatments have improved survival, many patients still develop resistance or relapse to therapy. This highlights the need to find new targets for more effective treatment outcomes. Our study focuses on a protein called SIRT6, which helps control DNA repair and cell growth and is found at high levels in melanoma. We reduced SIRT6 in melanoma cells using genetic tools and discovered that this slowed their growth and reduced their ability to survive. Using advanced techniques to analyze genes and proteins, we found that lowering SIRT6 turned off signals that promote cancer growth and activated pathways linked to cell death. These results suggest that SIRT6 plays a key role in melanoma progression and could be an important new target for future treatments.

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.