Calreticulin enhances gastric cancer metastasis by dimethylating H3K9 in the E-cadherin promoter region mediating by G9a
Lina Wang,
Jun Chen,
Qianfei Zuo,
Chunmei Wu,
Ting Yu,
Pengfei Zheng,
Hui Huang,
Jun Deng,
Lichao Fang,
Huamin Liu,
Chenghong Li,
Peiwu Yu,
Quanming Zou,
Junsong Zheng
Affiliations
Lina Wang
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Jun Chen
Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Army Medical University
Qianfei Zuo
National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University
Chunmei Wu
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Ting Yu
National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University
Pengfei Zheng
Department of medicinal chemistry, College of Pharmacy, Army Medical University
Hui Huang
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Jun Deng
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Lichao Fang
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Huamin Liu
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Chenghong Li
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Peiwu Yu
Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Army Medical University
Quanming Zou
National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University
Junsong Zheng
Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University
Abstract The latest study shows that gastric cancer (GC) ranked the fifth most common cancer (5.6%) with over 1 million estimated new cases annually and the fourth most common cause of cancer death (7.7%) globally in 2020. Metastasis is the leading cause of GC treatment failure. Therefore, clarifying the regulatory mechanisms for GC metastatic process is necessary. In the current study, we discovered that calreticulin (CALR) was highly expressed in GC tissues and related to lymph node metastasis and patient’s terrible prognosis. The introduction of CALR dramatically promoted GC cell migration in vitro and in vivo, while the repression of CALR got the opposite effects. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT) and is related to adhesion of cells. Additionally, we observed that CALR inhibition or overexpression regulated the expression of EMT markers (E-cadherin, ZO-1, Snail, N-cadherin, and ZEB1) and cellular adhesive moleculars (Fibronectin, integrin β1and MMP2). Mechanistically, our data indicated that CALR could mediate DNA methylation of E-cadherin promoter by interacting with G9a, a major euchromatin methyltransferase responsible for methylation of histone H3 on lysine 9(H3K9me2) and recruiting G9a to the E-cadherin promoter. Knockdown of G9a in CALR overexpressing models restored E-cadherin expression and blocked the stimulatory effects of CALR on GC cell migration. Taken together, these findings not only reveal critical roles of CALR medicated GC metastasis but also provide novel treatment strategies for GC.