title: Reduction of pancreatic cancer cell viability and induction of apoptosis mediated by siRNA targeting DNMT1 through suppression of total DNA methyltransferase activity.
abstract: Aberrant methylation leads to epigenetic changes in human genes that may cause carcinogenesis. DNA methyltransferase 1 (DNMT1) plays an important role in maintaining DNA methylation patterns during genomic DNA replication. To understand the role of this protein in pancreatic cancer cell growth and apoptosis, small interfering RNA (siRNA) oligonucleotides were used to knockdown DNMT1 expression in pancreatic cancer PaTu8988 cells. We found that the DNMT1 siRNA markedly decreased DNMT1 expression and total DNA methyltransferase activity in the cells. Upon the inhibition of DNMT1 expression, the proliferation of the tumor cells was inhibited. Tumor cell growth was arrested in the S-phase of the cell cycle and cells underwent apoptosis. The expression of p21 was up-regulated and the ratio of Bax/Bcl-2 expression was increased after DNMT1 knockdown in PaTu8988 cells. Furthermore, DNMT1 siRNA caused demethylation of the tumor suppressor gene hMLH1, resulting in its re-expression in PaTu8988 cells. The results of this study suggest that DNMT1 siRNA oligonucleotides are candidates for further evaluation as therapeutic tools for the clinical control of pancreatic cancer.
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Yi Qi
authors.initials: YQ
authors.lastname: Du
authors.forename: Dao-Jian
authors.initials: DJ
authors.lastname: Gao
authors.forename: Yu Qi
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Zhao Shen
authors.initials: ZS
authors.lastname: Li
authors.forename: You Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Yan Fang
authors.initials: YF
authors.lastname: Gong
authors.forename: Ping
authors.initials: P
authors.lastname: Xu