Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression,iScience

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Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression
iScience ( IF 4.6 ) Pub Date : 2024-02-01 , DOI: 10.1016/j.isci.2024.109011
Yajuan Zhang _{1,

2} , Yingwei Zhu ₃ , Ying Chen ₄ , Yanli Wang ₅ , Bing Liu ₂ , Yating Pan ₆ , Xinyi Liao ₆ , Jun Pan ₇ , Hong Gao ₂ , Weiwei Yang _{2,

8} , Guanzhen Yu _{6,

9}

Affiliation

Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Department of Gastroentrology, Jiangnan University Medical Center, Wuxi 214000, China.
Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200003, China.
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
Department of Medical Oncology, Cancer Center of Jinling Hospital, Nanjing 210002, China.
Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing 312366, China.

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 () expression by increasing DNA methylation at its promoter, thereby dampening the migration and metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of promoter.

中文翻译：

裂解的 PCDH9 的核易位通过下调 CDH2 表达损害胃癌转移

原钙粘蛋白9（PCDH9）的丢失与胃癌患者的转移和预后相关，但PCDH9受损的胃癌转移的分子机制尚不清楚。在这里，我们展示了 PCDH9 在胃癌细胞中被裂解。 PCDH9 的胞内结构域易位到细胞核中，与 DNA 甲基转移酶 1 (DNMT1) 相互作用并增加 DNMT1 活性。激活的DNMT1通过增加其启动子处的DNA甲基化来下调钙粘蛋白2()的表达，从而抑制胃癌细胞的迁移和转移。此外，核PCDH9的水平与CDH2的表达、淋巴结转移以及胃癌患者的预后相关。我们的发现证明了 PCDH9 通过促进启动子 DNA 甲基化来损伤胃癌转移的独特机制。

更新日期：2024-02-01

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