PPM1G Inhibits Epithelial - Mesenchymal Transition in Cholangiocarcinoma - Catalyzing TET1 Dephosphorylation for CLDN3 Promoter Destabilization

Sep 21, 2026

PPM1G is investigated as a regulator of TET1-mediated epigenetic control in cholangiocarcinoma. TET1, a key DNA demethylation enzyme, is highly expressed in CCA and linked to poor prognosis. Mechanistically, TET1 promotes CLDN3 transcription by targeting the CLDN3 promoter region for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing TET1 dephosphorylation, destabilizing TET1 and reducing its demethylation activity. Phosphatase inhibitors staurosporine and AZD0156 suppress EMT by inhibiting TET1 expression, supporting PPM1G as a therapeutic target to impair CCA progression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

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Introduction

Cholangiocarcinoma background and clinical challenges

Epigenetics and DNA methylation/demethylation

Role of TET1 in cancer and promoter demethylation

Targeting EMT via epigenetic modulation

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) PPM1G Inhibits Epithelial–Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter Wenzheng Liu, Yiyang Kuai, Da Wang, Junsheng Chen, Fei Xiong, Guanhua Wu, Qi Wang, Wenhua Huang, Yongqiang Qi, Bing Wang,* and Yongjun Chen* Ten–eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of diﬀerent types of cancers by regulating the expression of proto-oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin-3 (CLDN3) transcription by targeting the CLDN3 promoter region between −16 and 512 fordemethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation ofTET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter fordemethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation ofTET1, which diminishes the capacity ofTET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA. the second most common primary malignant tumor of the liver after hepatocellular carcinoma. [1] Epidemiological data indicate that the global incidence of cholangiocarcinoma has been gradually increasing over the past decade, with a poor prognosis. [2] A statistical analysis conducted by the National Comprehensive Cancer Network of the United States ofAmerica indicates that the 5 year overall survival rate for patients diagnosed with hepatoportal cholangiocarcinoma ranges from 20% to 42% . In comparison, the rate for those diagnosed with distal cholangiocarcinoma ranges from 16% to 52% . [3] The optimal treatment for cholangiocarcinoma is radical surgical resection. However, only 20–30% of patients diagnosed with cholangiocarcinoma are eligible for surgical resection. [4] Although combined radiotherapy can potentially delay disease progression in patients who cannot undergo surgical resection, the eﬀect remains 1. Introduction Cholangiocarcinoma (CCA) is a prevalent primary malignant neoplasm that arises from the epithelial cells of the bile ducts. It is limited. [5] The lack of speciﬁc molecular markers or targets for diagnosing and treating cholangiocarcinoma represents a significant challenge in medical research. Epigenetics is deﬁned as a heritable change in gene function that occurs without a change in the DNA sequence of the gene, W. Liu, Y. Kuai, D. Wang, J. Chen, G. Wu, Q. Wang, B. Wang, Y. Chen Department of Biliary-Pancreatic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Avenue, Wuhan, Hubei 430030, China E-mail: [2013TJ0575@hust.edu.cn](2013TJ0575@hust.edu.cn); [yjchen@tjh.tjmu.edu.cn](yjchen@tjh.tjmu.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202407323](https://doi.org/10.1002/advs.202407323)[ ](https://doi.org/10.1002/advs.202407323)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202407323 F. Xiong Department of General Surgery Beijing Friendship Hospital Capital Medical University Beijing 100050, China W. Huang Department of Emergency Tongji Hospital

FAQs

What role does TET1 play in cholangiocarcinoma?

TET1 is highly expressed in cholangiocarcinoma and is associated with poor prognosis. It promotes CLDN3 transcription by targeting the CLDN3 promoter region for demethylation.

How does PPM1G affect TET1 and downstream CLDN3 demethylation?

PPM1G acts as a protein dephosphorylase that dephosphorylates TET1. This destabilizes the TET1 protein, impairing its targeting of the CLDN3 promoter and reducing targeted demethylation needed for transcriptional activation.

How can EMT in cholangiocarcinoma be inhibited according to the study?

The study reports that phosphatase inhibitors staurosporine and AZD0156 inhibit epithelial-to-mesenchymal transition (EMT). They do so by suppressing TET1 expression, thereby disrupting the epigenetic pathway.

Sep 21, 2026

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