YY1 suppresses proliferation and migration of pancreatic ductal adenocarcinoma by regulating the CDKN3/MdM2/P53/P21 signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) is one of the malignant lethal tumors. It has been reported that the transcriptional regulator Yin Yang-1 (YY1) suppressed the invasion and metastasis of PDAC. However, the function of YY1 on proliferation and migration of pancreatic cancer remains to be clarified. In this study, we found that YY1 overexpression or knockdown can inhibit or promote the proliferation and migration of pancreatic cancer cells. Digital gene expression sequencing indicates that cyclin-dependent kinase inhibitor 3 (CDKN3) may be the candidate target gene of YY1. Then we found that YY1 can downregulate the expression of CDKN3 by directly binding to the promoter region of CDKN3. Silencing CDKN3 expression could inhibit the ability of cell proliferation and migration and overexpression of CDKN3 could restore the effects induced by YY1 overexpression in pancreatic cancer cells. The expression levels of YY1 and CDKN3 were negatively correlated in pancreatic cancer tissues and PDAC patients with higher levels of CDKN3 have poor prognosis. Vitro and vivo study show that CDKN3 can form a complex with MdM2-P53, thus leading to inhibiting the expression of P21, which is the target gene of P53, and finally facilitates the cell cycle to promote the proliferation of pancreatic cancer cells. Hence, YY1 can directly regulate the expression of CDKN3 and participate in the cycle of pancreatic cancer cells, which can inhibit the progression of pancreatic cancer. These results reveal that YY1-CDKN3-MDM2/P53-P21 axis is involved in pancreatic tumorigenesis, which may develop new methods for human pancreatic cancer therapy.