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.