Thymine DNA glycosylase as a novel target for melanoma

Pietro Mancuso, Rossella Tricarico, Vikram Bhattacharjee, Laura Cosentino, Yuwaraj Kadariya, Jaroslav Jelinek, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Richard A Katz, Dorjbal G Dorjsuren, Hongmao Sun, Anton Simeonov, Antonio Giordano, Joseph R Testa, Guillaume Davidson, Irwin Davidson, Lionel Larue, Robert W SobolTimothy J Yen, Alfonso Bellacosa

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)3710-3728
Number of pages19
JournalOncogene
Volume38
Issue number19
DOIs
StatePublished - Apr 2019

Keywords

  • Animals
  • Cell Cycle/genetics
  • Cell Line, Tumor
  • Cell Proliferation/genetics
  • Cytosine/analogs & derivatives
  • DNA Methylation
  • Enzyme Inhibitors/pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma/drug therapy
  • Melanoma, Experimental/genetics
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Molecular Targeted Therapy/methods
  • Thymine DNA Glycosylase/antagonists & inhibitors
  • Xenograft Model Antitumor Assays

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