title: YY1 suppresses FEN1 over-expression and drug resistance in breast cancer.
abstract: BACKGROUND
  Drug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers.
  
  
  METHODS
  To reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients.
  
  
  RESULTS
  We observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.
  
  
  CONCLUSIONS
  Altogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China. lch1239wang@126.com.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China. lizhou@coh.org.|Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. lizhou@coh.org.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Departments of Medical Oncology and Thoracic Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China. lizhi2008@hotmail.com.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China. elaine.zt@gmail.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China. weliu@coh.org.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. zliu@coh.org.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. yyuan@coh.org.
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. mfsu1993@gmail.com.
authors.forename: Fan
authors.initials: F
authors.lastname: Su
authors.affiliation: Departments of Medical Oncology and Thoracic Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China. xulu0001@163.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Departments of Medical Oncology and Thoracic Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China. gracie-w@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Medical Oncology and Thoracic Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China. zhouxiaotong0081@hotmail.com.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: College of Agricultural Sciences and Biotechnology, Zhejiang University, Hangzhou, China. Xuhong1685@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: College of Agricultural Sciences and Biotechnology, Zhejiang University, Hangzhou, China. yjhua@zju.edu.cn.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Hua
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, China. yingjiewang@zju.edu.cn.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. lzheng@coh.org.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Departments of Medical Oncology and Thoracic Surgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China. tengyuee0517@163.com.
authors.forename: Yue-E
authors.initials: YE
authors.lastname: Teng
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA. bshen@coh.org.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002460:Cell Line; D017124:Conserved Sequence; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D045585:Flap Endonucleases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D059372:Nucleotide Motifs; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050986:YY1 Transcription Factor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050986:YY1 Transcription Factor; D045585:Flap Endonucleases; C468317:FEN1 protein, human