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

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 interplay forms a positive transcriptional feedback loop between NKX2-5/LHX1 and UHRF1, thus promoting the overexpression of all three genes and ultimately facilitating tumor growth. Notably, concurrent inhibition of UHRF1 and DNMTs impedes tumor growth by suppressing NKX2-5 and LHX1 expression. Overall, this study identifies a positive feedback regulatory circuitry underlying the UMR hypermethylation-mediated activation of oncogenic drivers in ESCC and proposes a promising therapeutic strategy for ESCC patients.