title: TGF-β1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma.
abstract: TGF-β1, a potent EMT (epithelial-mesenchymal transition) inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including esophageal squamous cell carcinoma (ESCC). TIP30 (30kDa HIV-1 Tat interacting protein) is a putative tumor metastasis suppressor. Here, we found TIP30 was decreased in cells undergoing EMT induced by TGF-β1, an occurrence that was related to promoter hypermethylation. TGF-β1 induced TIP30 hypermethylation via increasing DNMT1 and DNMT3A expression, which could be restored by TGF-β antibodies. In our in vitro and in vivo studies, we showed that silence of TIP30 led to EMT, enhanced migrative and invasive abilities of ESCC cells, promoted tumor metastasis in xenografted mice; alternatively, overexpression of TIP30 inhibited TGF-β1-induced EMT, and metastatic abilities of ESCC cells. Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of β-catenin in an AKT-dependent manner, which further resulted in the initiation of EMT. Consistently, TIP30 was frequently methylated and downregulated in ESCC patients. Loss of TIP30 correlated with nuclear β-catenin and aberrant E-cadherin expression. TIP30 was a powerful marker in predicting the prognosis of ESCC. Taken together, our results suggest a novel and critical role of TIP30 involved in TGF-β1-induced activation of AKT/β-catenin signaling and ESCC metastasis.
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Bu
authors.affiliation: The 150 Hospital of Chinese PLA, Luoyang, P.R.China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.
authors.forename: Shukun
authors.initials: S
authors.lastname: Chen
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: The 150 Hospital of Chinese PLA, Luoyang, P.R.China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Ma
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Pan
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology & Institute of Oncologic Pathology, Shantou University Medical College, Shantou, P.R.China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology & Institute of Oncologic Pathology, Shantou University Medical College, Shantou, P.R.China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology & Institute of Oncologic Pathology, Shantou University Medical College, Shantou, P.R.China.
authors.forename: Enmin
authors.initials: E
authors.lastname: Li
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.|Department of Pharmacy, Liaocheng University, Liaocheng, P.R. China.
authors.forename: Geng
authors.initials: G
authors.lastname: Kou
authors.affiliation: Department of Pharmacy, Liaocheng University, Liaocheng, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pharmacy, Liaocheng University, Liaocheng, P.R. China.
authors.forename: Shangjing
authors.initials: S
authors.lastname: Guo
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China.|International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China.|Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China.|Department of Pharmacy, Liaocheng University, Liaocheng, P.R. China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D034622:RNA Interference; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D000123:Acetyltransferases; C111246:HTATIP2 protein, human