NKX2-5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation.

ABSTRACT: DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation of under-methylated regions (UMRs) within gene bodies is involved in the activation of oncogenic homeobox genes, particularly NKX2-5 and LHX1, in esophageal squamous cell carcinoma (ESCC). Mechanistically, NKX2-5 and LHX1 synergistically bind to the promoter region of UHRF1, thereby augmenting its transcription. In turn, UHRF1 orchestrates the recruitment of DNMT1/DNMT3A, alongside NKX2-5 and LHX1, to the UMRs of these genes, thereby increasing DNA methylation levels and their expression. This intricate

SUBMITTER: Li X 

PROVIDER: S-EPMC12120717 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature