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Oncogene. 2019 May;38(19):3710-3728. doi: 10.1038/s41388-018-0640-2. Epub 2019 Jan 23.

Thymine DNA glycosylase as a novel target for melanoma.

Author information

1
Cancer Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
2
Department of Medical Biotechnologies, Universita' degli Studi di Siena, Siena, Italy.
3
Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, 91405, Orsay, France.
4
Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
5
Fels Institute for Cancer and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
6
Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
7
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
8
Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
9
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404, Illkirch, France.
10
Equipe Labellisée Ligue Contre le Cancer, Orsay, France.
11
University Paris-Sud, University Paris-Saclay, CNRS UMR3347, Orsay, France.
12
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
13
Cancer Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. Alfonso.Bellacosa@fccc.edu.

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.

PMID:
30674989
PMCID:
PMC6563616
[Available on 2019-07-23]
DOI:
10.1038/s41388-018-0640-2

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