Thymine DNA glycosylase as a novel target for melanoma
Authors: Anton Simeonov
Lionel Larue
Alfonso Bellacosa
Jaroslav Jelinek
Antonio Giordano
Irwin Davidson
Guillaume Davidson
Joseph R Testa
Rossella Tricarico
Robert W Sobol
Emmanuelle Nicolas
Vikram Bhattacharjee
Margret Einarson
Neil Beeharry
Karthik Devarajan
Dorjbal G Dorjsuren
Timothy J Yen
Laura Cosentino
Pietro Mancuso
Hongmao Sun
Richard A Katz
Yuwaraj Kadariya
Journal: Oncogene (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Melanoma; NCI; cancer; BRAF/MEK/ERK signaling pathway; immune checkpoints
Affiliations: Cancer Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA., Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA., Fels Institute for Cancer and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, 19140, USA., Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA., Department of Medical Biotechnologies, Universita' degli Studi di Siena, Siena, Italy., Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404, Illkirch, France., Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, 91405, Orsay, France., Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA., Cancer Epigenetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA. .

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. 

Retracted: No

PubPeer comments:
 There appears to be a repeated image in Figure 3i, after 180-degree rotation. Could the authors please check? *** ![file] ,