DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis
Sunwang Xu1,2, Zhiqing Yuan1, Cen Jiang3
1Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China.
Abstract:
Gallbladder cancer (GBC) is an extremely lethal malignancy with aggressive behaviors, including liver or distant metastasis; however, the underlying mechanisms driving the metastasis of GBC remain poorly understood. In this study, it is found that DNA methyltransferase DNMT3A is highly expressed in GBC tumor tissues compared to matched adjacent normal tissues. Clinicopathological analysis shows that DNMT3A is positively correlated with liver metastasis and poor overall survival outcomes in patients with GBC. Functional analysis confirms that DNMT3A promotes the metastasis of GBC cells in a manner dependent on its DNA methyltransferase activity. Mechanistically, DNMT3A interacts with and is recruited by YAP/TAZ to recognize and access the CpG island within the CDH1 promoter and generates hypermethylation of the CDH1 promoter, which leads to transcriptional silencing of CDH1 and accelerated epithelial-to-mesenchymal transition. Using tissue microarrays, the association between the expression of DNMT3A, YAP/TAZ, and CDH1 is confirmed, which affects the metastatic ability of GBC. These results reveal a novel mechanism through which DNMT3A recruitment by YAP/TAZ guides DNA methylation to drive GBC metastasis and provide insights into the treatment of GBC metastasis by targeting the functional connection between DNMT3A and YAP/TAZ.
Insights
DNA methyltransferase DNMT3A promotes gallbladder cancer metastasis by interacting with YAP/TAZ to silence CDH1. This finding reveals a new mechanism for gallbladder cancer spread and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Gallbladder cancer (GBC) is a lethal malignancy with poorly understood metastatic mechanisms.
- Liver and distant metastasis are common aggressive behaviors in GBC.
- Identifying drivers of GBC metastasis is crucial for improving patient outcomes.
Purpose of the Study:
- To elucidate the role of DNA methyltransferase DNMT3A in GBC metastasis.
- To investigate the molecular mechanisms underlying DNMT3A-driven GBC cell metastasis.
- To explore the potential of targeting the DNMT3A-YAP/TAZ interaction for GBC treatment.
Main Methods:
- Analysis of DNMT3A expression in GBC tissues.
- Clinicopathological correlation of DNMT3A expression with metastasis and survival.
- Functional assays to assess DNMT3A's role in GBC cell metastasis.
- Mechanistic studies involving YAP/TAZ, CDH1 promoter methylation, and epithelial-to-mesenchymal transition (EMT).
- Tissue microarray analysis to validate molecular associations.
Main Results:
- DNMT3A is highly expressed in GBC tissues and correlates with liver metastasis and poor survival.
- DNMT3A promotes GBC metastasis via its DNA methyltransferase activity.
- DNMT3A, recruited by YAP/TAZ, hypermethylates the CDH1 promoter, silencing CDH1 and promoting EMT.
- Expression of DNMT3A, YAP/TAZ, and CDH1 is associated with GBC metastatic ability.
Conclusions:
- DNMT3A, guided by YAP/TAZ, drives GBC metastasis through CDH1 promoter hypermethylation and EMT.
- This study reveals a novel mechanism for GBC metastasis.
- Targeting the DNMT3A-YAP/TAZ functional connection offers potential therapeutic strategies for GBC metastasis.
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