title: Silencing of MBD1 reverses pancreatic cancer therapy resistance through inhibition of DNA damage repair.
abstract: High resistance to traditional chemo- and radiotherapies contributes to the poor prognosis of pancreatic cancer (PC). Methyl-CpG binding domain protein 1 (MBD1), which plays an important role in disease progression, contributes to the drug resistance of PC cells; however, the mechanism underlying the drug resistance endowed by MBD1 remains unknown. In this study, we found that MBD1 was recruited to DNA damage sites under DNA damage conditions. Silencing of MBD1 significantly impaired activation of the DNA damage checkpoint response and inhibited DNA repair capacity. MBD1 binds mediator of DNA damage checkpoint protein 1 (MDC1), which is induced by radiation and regulates NBS1 activation in the presence of DNA damage repair. Knockdown of MBD1 significantly increased the sensitivity of cells to radiation and cisplatin (diamindichloridoplatin, DDP) in vitro. Importantly, the function of MBD1 in regulating chemoradioresistance is also partially dependent on DNA damage repair. Thus, we hypothesize that MBD1 may promote PC chemoradioresistance by regulating PC cell fate in the presence of DNA damage. Collectively, these findings reveal an important function of MBD1 in DNA repair and mediation of chemoradioresistance of cancer cells. Moreover, this study suggests that MBD1 is a promising molecular target for sensitizing resistant PC tumor cells to chemoradiotherapy.
authors.affiliation: Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhu
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cui
authors.forename: Leon
authors.initials: L
authors.lastname: Chen
authors.forename: Shunrong
authors.initials: S
authors.lastname: Ji
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.forename: Wantong
authors.initials: W
authors.lastname: Yao
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Jiang
authors.initials: J
authors.lastname: Long
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D002843:Chromatin / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C066141:MBD1 protein, human; C413163:MDC1 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D002945:Cisplatin