Key Takeaways & Executive Findings
- •• ZNF154 is downregulated in cervical cancer via promoter methylation, correlating with poor prognosis. • Overexpression of ZNF154 suppresses cervical cancer cell proliferation and migration. • ZNF154 inhibits Wnt/β-catenin signaling by upregulating NLK, a novel mechanistic link. • ZNF154 represents a potential therapeutic target for cervical cancer treatment.
Abstract
Cervical cancer represents a significant global health concern affecting women. The global cancer burden data published by the World Health Organization’s International Agency for Research on Cancer (IARC) indicated that the incidence and mortality of cervical cancer were the fourth most common malignancy in females worldwide in 2022 [1]. DNA methylation is recognized as a pivotal epigenetic mechanism for gene silencing, which may accumulate with disease severity [2]. Hypermethylation has been discovered in several tumor suppressor gene (TSG) promoters in human cancers, and further understanding of gene silencing mechanisms has led more studies to consider epigenetic disruption as an important mechanism leading to the silencing of tumor suppressor genes in tumor development [3]. Recent studies have reported that methylation of the zinc finger protein 154 (ZNF154) gene plays an oncogenic role in the development of several cancers [4]. ZNF154 has been shown to inhibit tumor cell proliferation in nasopharyngeal carcinoma by altering the expression of E-cadherin through the Wnt/β-catenin pathway, thereby inhibiting epithelial-to-mesenchymal transition (EMT) [5]. He et al. [6] demonstrated that ZNF154 could transcriptionally regulate the expressions of tumor suppressor genes involved in the cell cycle, the p53 signaling pathway, and the Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma. Thus, ZNF154 can be considered a novel cancer biomarker of clinical significance. However, the role of ZNF154 in cervical cancer remains unclear. In the present study, we analyzed ZNF154 expression and its potential biological functions and molecular mechanisms in cervical cancer. ZNF154 was found to be downregulated by promoter methylation in cervical cancer tissue. Its overexpression in cervical cancer cells inhibited cell proliferation and migration. Mechanistically, ZNF154 inhibits the Wnt/β-catenin signaling pathway by directly targeting and positively modulating Nemo-like kinase (NLK) activity. Collectively, our findings indicate the crucial role of ZNF154 in the proliferation and migration of cervical cancer cells, indicating that ZNF154 may serve as a promising target for future therapeutic development.
1. Introduction
Cervical cancer represents a significant global health concern affecting women. The global cancer burden data published by the World Health Organization’s International Agency for Research on Cancer (IARC) indicated that the incidence and mortality of cervical cancer were the fourth most common malignancy in females worldwide in 2022 [1]. DNA methylation is recognized as a pivotal epigenetic mechanism for gene silencing, which may accumulate with disease severity [2]. Hypermethylation has been discovered in several tumor suppressor gene (TSG) promoters in human cancers, and further understanding of gene silencing mechanisms has led more studies to consider epigenetic disruption as an important mechanism leading to the silencing of tumor suppressor genes in tumor development [3].
Recent studies have reported that methylation of the zinc finger protein 154 (ZNF154) gene plays an oncogenic role in the development of several cancers [4]. ZNF154 has been shown to inhibit tumor cell proliferation in nasopharyngeal carcinoma by altering the expression of E-cadherin through the Wnt/β-catenin pathway, thereby inhibiting epithelial-to-mesenchymal transition (EMT) [5]. He et al. [6] demonstrated that ZNF154 could transcriptionally regulate the expressions of tumor suppressor genes involved in the cell cycle, the p53 signaling pathway, and the Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma. Thus, ZNF154 can be considered a novel cancer biomarker of clinical significance. However, the role of ZNF154 in cervical cancer remains unclear.
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Chulan Yang, Hongyu Zhao, Jing Tuo, Wei Zhao, Zhiwei Zhang, Zemin Pan, Lianghai Wang, Haixuan Zhao, Songhua Zhao, Hongtao Li (2026). Zinc finger protein 154 inhibits the growth and metastasis of cervical cancer cells through inhibiting Wnt/β-catenin signaling by upregulating NLK. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025118
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Frequently Asked Questions
What is the role of ZNF154 in cervical cancer?
ZNF154 acts as a tumor suppressor in cervical cancer by inhibiting cell proliferation and migration through the Wnt/β-catenin signaling pathway via upregulation of NLK.
How is ZNF154 downregulated in cervical cancer?
ZNF154 expression is downregulated due to promoter hypermethylation, as demonstrated by lower expression in tumor tissues and increased expression upon treatment with a DNA methyltransferase inhibitor.
What is the mechanism by which ZNF154 inhibits Wnt/β-catenin signaling?
ZNF154 directly targets and positively modulates Nemo-like kinase (NLK) activity, which in turn inhibits the Wnt/β-catenin signaling pathway.
What are the clinical implications of this study?
The findings suggest that ZNF154 could serve as a promising therapeutic target for cervical cancer treatment, and its methylation status may be a potential biomarker for diagnosis or prognosis.
What methods were used to analyze ZNF154 expression?
The study used TCGA and GEO databases, immunohistochemistry on patient samples, and qRT-PCR on cervical cancer cell lines treated with 5-Aza-dC to assess expression and methylation effects.
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