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ALKBH4 Stabilization Is Required for Arsenic-Induced 6mA DNA Methylation Inhibition, Keratinocyte Malignant Transformation, and Tumorigenicity.
Cui, Yan-Hong; Wilkinson, Emma; Peterson, Jack; He, Yu-Ying.
Afiliación
  • Cui YH; Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • Wilkinson E; Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • Peterson J; The College, Biological Science Division, University of Chicago, Chicago, IL 60637, USA.
  • He YY; Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Water (Basel) ; 14(22)2022 Nov 02.
Article en En | MEDLINE | ID: mdl-37207134
Inorganic arsenic is one of the well-known human skin carcinogens. However, the molecular mechanism by which arsenic promotes carcinogenesis remains unclear. Previous studies have established that epigenetic changes, including changes in DNA methylation, are among the critical mechanisms that drive carcinogenesis. N6-methyladenine (6mA) methylation on DNA is a widespread epigenetic modification that was initially found on bacterial and phage DNA. Only recently has 6mA been identified in mammalian genomes. However, the function of 6mA in gene expression and cancer development is not well understood. Here, we show that chronic low doses of arsenic induce malignant transformation and tumorigenesis in keratinocytes and lead to the upregulation of ALKBH4 and downregulation of 6mA on DNA. We found that reduced 6mA levels in response to low levels of arsenic were mediated by the upregulation of the 6mA DNA demethylase ALKBH4. Moreover, we found that arsenic increased ALKBH4 protein levels and that ALKBH4 deletion impaired arsenic-induced tumorigenicity in vitro and in mice. Mechanistically, we found that arsenic promoted ALKBH4 protein stability through reduced autophagy. Together, our findings reveal that the DNA 6mA demethylaseALKBH4 promotes arsenic tumorigenicity and establishes ALKBH4 as a promising target for arsenic-induced tumorigenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Water (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Water (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza