Methyl-CpG-binding domain 3 inhibits stemness of pancreatic cancer cells via Hippo signaling

Abstract

Methyl-CpG-binding domain 3 (MBD3), as an induced stem cells reprogramming barrier, has an abnormal expression in various prevalent malignancies. However, in pancreatic cancer cell stemness, the roles of MBD3 remain unclear. In our study, the effects of MBD3 were investigated on the proliferation, stemness and the underlying mechanism in pancreatic cancer cells. Firstly, MBD3 knockdown was proved to promote proliferation and sphere formation of pancreatic cancer cells and tumorigenesis, while MBD3 upregulation inhibited the above results. Also, MBD3 downregulation notably increased stemness markers level of OCT4, NANOG and SOX2, and MBD3 upregulation resulted in the opposite effects. Mechanically, it was found that MBD3 involved in activation of Hippo pathway. There was a negative correlation between MBD3 and YAP expression in TCGA database. MBD3 knockdown improved YAP expression, and promoted YAP nuclear translocation increased TEAD luciferase activity, while MBD3 overexpression reversed the above results. Further evidence revealed that YAP could bind to MBD3, and decreased MBD3 expression. Collectively, MBD3 bound to YAP to significantly inhibit proliferation and weaken stemness maintenance in pancreatic cancer cells, as well as reduce tumorigenesis via Hippo signaling. Thus, MBD3 may serve as a potential molecular biomarker for exploring new therapeutic strategies to treat pancreatic cancer.

Keywords: Hippo signaling; MBD3; Pancreatic cancer; Proliferation; Stemness.