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Mancuso P , Tricarico R , Bhattacharjee V , Cosentino L , Kadariya Y , Jelinek J , Nicolas E , Einarson M , Beeharry N , Devarajan K , Katz RA , Dorjsuren DG , Sun H , Simeonov A , Giordano A , Testa JR , Davidson G , Davidson I , Larue L , Sobol RW , Yen TJ , Bellacosa A
Thymine DNA glycosylase as a novel target for melanoma
Oncogene. 2019 May;38(19) :3710-3728
PMID: 30674989    PMCID: PMC6563616    URL: https://www.ncbi.nlm.nih.gov/pubmed/30674989
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Abstract
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.
Notes
Mancuso, Pietro Tricarico, Rossella Bhattacharjee, Vikram Cosentino, Laura Kadariya, Yuwaraj Jelinek, Jaroslav Nicolas, Emmanuelle Einarson, Margret Beeharry, Neil Devarajan, Karthik Katz, Richard A Dorjsuren, Dorjbal G Sun, Hongmao Simeonov, Anton Giordano, Antonio Testa, Joseph R Davidson, Guillaume Davidson, Irwin Larue, Lionel Sobol, Robert W Yen, Timothy J Bellacosa, Alfonso eng CA191956/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA78412/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA175691/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA150492/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA148629/U.S. Department of Health & Human Services | National Institutes of Health (NIH) ES025138/U.S. Department of Health & Human Services | National Institutes of Health (NIH) R21 CA191956/CA/NCI NIH HHS/ R01 CA175691/CA/NCI NIH HHS/ R01 CA078412/CA/NCI NIH HHS/ R43 ES025138/ES/NIEHS NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ R01 CA148629/CA/NCI NIH HHS/ England Oncogene. 2019 May;38(19):3710-3728. doi: 10.1038/s41388-018-0640-2. Epub 2019 Jan 23.