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Thymine DNA glycosylase as a novel target for melanoma
Mancuso, P Tricarico, R Bhattacharjee, V Cosentino, L Kadariya, Y Jelinek, J Nicolas, E Einarson, M Beeharry, N Devarajan, K
Mancuso, P
Tricarico, R
Bhattacharjee, V
Cosentino, L
Kadariya, Y
Jelinek, J
Nicolas, E
Einarson, M
Beeharry, N
Devarajan, K
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Genre
Journal Article
Date
2019-05-09
Advisor
Committee member
Group
Department
Subject
Animals
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cytosine
DNA Methylation
Enzyme Inhibitors
Female
Gene Expression Regulation, Neoplastic
Humans
Melanoma
Melanoma, Experimental
Mice, Knockout
Mice, SCID
Mice, Transgenic
Molecular Targeted Therapy
Thymine DNA Glycosylase
Xenograft Model Antitumor Assays
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cytosine
DNA Methylation
Enzyme Inhibitors
Female
Gene Expression Regulation, Neoplastic
Humans
Melanoma
Melanoma, Experimental
Mice, Knockout
Mice, SCID
Mice, Transgenic
Molecular Targeted Therapy
Thymine DNA Glycosylase
Xenograft Model Antitumor Assays
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DOI
10.1038/s41388-018-0640-2
Abstract
© 2019, The Author(s). Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signaling pathway and immune checkpoints. As drug resistance remains a major obstacle to treatment success, advanced therapeutic approaches based on novel targets are still urgently needed. We reasoned that the base excision repair enzyme thymine DNA glycosylase (TDG) could be such a target for its dual role in safeguarding the genome and the epigenome, by performing the last of the multiple steps in DNA demethylation. Here we show that TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence, and death by mitotic alterations; alters the transcriptome and methylome; and impairs xenograft tumor formation. Importantly, untransformed melanocytes are minimally affected by TDG knockdown, and adult mice with conditional knockout of Tdg are viable. Candidate TDG inhibitors, identified through a high-throughput fluorescence-based screen, reduced viability and clonogenic capacity of melanoma cell lines and increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, indicating successful on-target activity. These findings suggest that TDG may provide critical functions specific to cancer cells that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy.
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Springer Science and Business Media LLC
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Oncogene
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