Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor

TLDR

DNA methylation of tumor suppressor genes frequently silences transcription in cancer, yet the mechanisms that confer methylation specificity remain unclear. The leukemia‑promoting PML‑RAR fusion protein recruits DNA methyltransferases to target promoters, inducing hypermethylation and silencing that drive leukemogenesis, while retinoic acid reverses these changes and restores normal phenotype, linking genetic and epigenetic alterations in early cancer development.

Abstract

DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.