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
Affiliations
Yajuan Zhang
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; Corresponding author
Yingwei Zhu
Department of Gastroentrology, Jiangnan University Medical Center, Wuxi 214000, China
Ying Chen
Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200003, China
Yanli Wang
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Bing Liu
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
Yating Pan
Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
Xinyi Liao
Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
Jun Pan
Department of Medical Oncology, Cancer Center of Jinling Hospital, Nanjing 210002, China
Hong Gao
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
Weiwei Yang
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; 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; Corresponding author
Guanzhen Yu
Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing 312366, China; Corresponding author
Summary: 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.
