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

Yajuan Zhang; Yingwei Zhu; Ying Chen; Yanli Wang; Bing Liu; Yating Pan; Xinyi Liao; Jun Pan; Hong Gao; Weiwei Yang; Guanzhen Yu

doi:10.1016/j.isci.2024.109011

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

iScience. 2024 Feb 1;27(2):109011. doi: 10.1016/j.isci.2024.109011. eCollection 2024 Feb 16.

Authors

Yajuan Zhang^{1

2}, Yingwei Zhu³, Ying Chen⁴, Yanli Wang⁵, Bing Liu², Yating Pan⁶, Xinyi Liao⁶, Jun Pan⁷, Hong Gao², Weiwei Yang^{2

8}, Guanzhen Yu^{6

9}

Affiliations

¹ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
² 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.
³ Department of Gastroentrology, Jiangnan University Medical Center, Wuxi 214000, China.
⁴ Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200003, China.
⁵ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁶ Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
⁷ Department of Medical Oncology, Cancer Center of Jinling Hospital, Nanjing 210002, China.
⁸ 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.
⁹ Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing 312366, China.

Abstract

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 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo 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 CDH2 promoter.

Keywords: Biochemistry; Biological sciences; Cancer; Cell biology; Natural sciences.