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<p>Accumulating evidence demonstrates that the silencing of tumor suppressor genes by aberrant DNA methylation contributes to the initiation and progression of ovarian cancer (OC), while the systemic methylation profile and the key driver methylation events need to be further explored. Here, by analysing public databases and our resources, we identified the hypermethylation of <i>ZNF154</i> promoter as a key driver of OC malignancy, which was mediated by the DNA methyltransferase complex DNMT1/UHRF1. Using CRISPR/dCas9-TET1CD, a tool for targeted demethylation, we successfully decreased the methylation level of <i>ZNF154</i> promoter and reactivated ZNF154 expression, which in turn inhibited the proliferation, migration, and invasion of OC cells. Mechanistically, ZNF154 interacted with KAP1 and directly bound to the <i>ROMO1</i> promoter, transcriptionally repressing ROMO1 expression, thereby reducing MMP2 and phosphorylated ERK to impede OC progression. Clinically, <i>ZNF154</i> hypermethylation was correlated with its reduced expression and poor prognosis in OC patients. These findings underscore a pivotal role of aberrant <i>ZNF154</i> methylation in OC pathogenesis and highlight its potential as both a therapeutic target and a prognostic biomarker for OC patients.</p>

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Hypermethylation of ZNF154 promotes malignant potential of ovarian cancer cells by diminishing ZNF154/KAP1-mediated ROMO1 repression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月2日

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  • Mingbiao Wei,
  • Yuxia Xu,
  • Ling Deng,
  • Wei Wei,
  • Dongyi Ling,
  • Shanshan Zhen,
  • Ran Zhou,
  • Wenjian Cen,
  • Xu Zhang,
  • Mayan Huang,
  • Jundong Li,
  • Shumei Yan,
  • Qin Li,
  • Ziming Du

摘要

Accumulating evidence demonstrates that the silencing of tumor suppressor genes by aberrant DNA methylation contributes to the initiation and progression of ovarian cancer (OC), while the systemic methylation profile and the key driver methylation events need to be further explored. Here, by analysing public databases and our resources, we identified the hypermethylation of ZNF154 promoter as a key driver of OC malignancy, which was mediated by the DNA methyltransferase complex DNMT1/UHRF1. Using CRISPR/dCas9-TET1CD, a tool for targeted demethylation, we successfully decreased the methylation level of ZNF154 promoter and reactivated ZNF154 expression, which in turn inhibited the proliferation, migration, and invasion of OC cells. Mechanistically, ZNF154 interacted with KAP1 and directly bound to the ROMO1 promoter, transcriptionally repressing ROMO1 expression, thereby reducing MMP2 and phosphorylated ERK to impede OC progression. Clinically, ZNF154 hypermethylation was correlated with its reduced expression and poor prognosis in OC patients. These findings underscore a pivotal role of aberrant ZNF154 methylation in OC pathogenesis and highlight its potential as both a therapeutic target and a prognostic biomarker for OC patients.