TET1 promotes cisplatin-resistance via demethylating the vimentin promoter in ovarian cancer.
The development of chemo-resistance impairs the outcome of the first line platinum-based chemotherapies for ovarian cancer. Deregulation of DNA methylation/demethylation provides a critical mechanism for the occurrence of chemo-resistance. The ten-eleven translocation (TET) family of dioxygenases including TET1/2/3 plays an important part in DNA demethylation, but their roles in cisplatin resistance have not been elucidated. Using cisplatin-sensitive and cisplatin-resistant ovarian cancer cell models, we found that TET1 was significantly upregulated in cisplatin-resistant CP70 cells compared with that in cisplatin-sensitive A2780 cells. Ectopic expression of TET1 in A2780 cells promoted cisplatin resistance and decreased cytotoxicity induced by cisplatin, while inhibition of TET1 by siRNA transfection in CP70 cells attenuated cisplatin resistance and enhanced cytotoxicity of cisplatin. Increased TET1 induced re-expression of vimentin through active DNA demethylation, and cause partial epithelial-to-mesenchymal (EMT) in A2780 cells. Contrarily, knocking down of TET1 in CP70 cells reduced vimentin expression and reversed EMT process. Immunohistochemical analysis of TET1 in human ovarian cancer tissues revealed that TET1 existed in nucleus and cytoplasm in ovarian cancer tissues. And the expression of nuclear TET1 was positively correlated with residual tumor and chemotherapeutic response. Thus, TET1 expression causes resistance to cisplatin and one of the targets of TET1 action is vimentin in ovarian cancer.
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Xi
X
Han
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Yuanyuan
Y
Zhou
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Yuanyi
Y
You
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Jiaojiao
J
Lu
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Lijie
L
Wang
Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Huilian
H
Hou
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Jing
J
Li
Center for Laboratory Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Wei
W
Chen
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Le
L
Zhao
Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Xu
X
Li
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000502:physiology*; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014746:Vimentin / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D014746:Vimentin; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D002945:Cisplatin
cisplatin; demethylation; ovarian cancer