Dataset Information

Mechanisms of the antiproliferative effects of SIRT6 inhibition in melanoma: A multi-omics analysis

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Mary Ndiaye

LAB HEAD: Nihal Ahmad

PROVIDER: PXD073999 | Pride | 2026-03-30

REPOSITORIES: pride

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Dataset's files

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			Action	DRS
	20180509_A375_shSIRT6_1_rep1.msf	Msf
	20180509_A375_shSIRT6_1_rep1.raw	Raw
	20180509_A375_shSIRT6_1_rep2.msf	Msf
	20180509_A375_shSIRT6_1_rep2.raw	Raw
	20180509_A375_shSIRT6_2_rep1.msf	Msf

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Publications

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

Anaya Aldrete Karla B KB Muntaqua Durdana D Garcia-Peterson Liz M LM Ndiaye Mary A MA Nam Jeong Ha JH Ahmad Nihal N

Cancers 20260211 4

<h4>Background/objectives</h4>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-p ...[more]

PMID: 41749843

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Project description:Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or N-RAS oncogene and express markers of senescence, including p16. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 20-30% of melanoma are thought to arise in association with a pre-existing nevus. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. We set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as cyclin D1 and c-myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, cyclin D1 and c-myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signalling in nevi correlated inversely with nevus maturation, an established dermatopathological correlate of clinical benignancy. Single cell analyses of lone epidermal melanocytes and nevus melanocytes showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16-positive non-malignant melanocytes. We conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of clinical benignancy, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi. We used RNA-Seq to detail the global programme of gene expression in human melanoma cell lines