title: Up-regulation of MBD1 promotes pancreatic cancer cell epithelial-mesenchymal transition and invasion by epigenetic down-regulation of E-cadherin.
abstract: Methyl-CpG binding domain protein 1 (MBD1) has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression and development. It is also predicted that MBD1 might be involved in tumor development and progression. However, whether and how MBD1 is involved in tumorigenesis, especially in pancreatic cancer (PC), is currently unknown. We found that MBD1 was significantly up-regulated in PC tissues compared with the surrounding normal tissues according to RT-PCR data. Tissue microarray (TMA) based immunohistochemical study from 58 surgically resected PC specimens indicated that higher MBD1 expression correlated with lymph node metastasis and poor survival in PC patients. Gain- and loss-of-function studies in vitro validated MBD1 as a potent oncogene promoting PC cell invasion as well as epithelial-mesenchymal transition (EMT). Mechanistically, MBD1 is associated with Twist and NAD-dependent deacetylase sirtuin-1 (SIRT1), thereby forming the Twist-MBD1-SIRT1 complex on the CDH1 promoter, which resulted in reduced E-cadherin transcription activity and increased cell EMT ability. Significantly, targeting MBD1 reversed the EMT phenotype of PC and restored sensitivity to chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in PC invasion and metastasis by providing a molecular mechanism underlying MBD1-promoted EMT. Thus MBD1 may serve as a potential therapeutic target for PC.
authors: Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Fudan University, 270 Dong An Road, Shanghai 200032, China.
authors: J
authors: J
authors: Xu
authors: W
authors: W
authors: Zhu
authors: W
authors: W
authors: Xu
authors: W
authors: W
authors: Yao
authors: B
authors: B
authors: Zhang
authors: Y
authors: Y
authors: Xu
authors: S
authors: S
authors: Ji
authors: C
authors: C
authors: Liu
authors: J
authors: J
authors: Long
authors: Q
authors: Q
authors: Ni
authors: X
authors: X
authors: Yu
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000378:metabolism; D013534:Survival; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D051879:Twist-Related Protein 1 / Q000378:metabolism; D015854:Up-Regulation; D000093542:Gemcitabine
chemical_list: D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; C513384:CDH1 protein, human; D015820:Cadherins; D004268:DNA-Binding Proteins; C066141:MBD1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D003841:Deoxycytidine; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000093542:Gemcitabine