title: Enhancer of rudimentary homolog regulates DNA damage response in hepatocellular carcinoma.
abstract: We previously demonstrated that the enhancer of rudimentary homolog (ERH) gene is required for the expression of multiple cell cycle and DNA damage response (DDR) genes. The present study investigated the role of ERH and its target DNA damage repair genes in hepatocellular carcinoma cells. We observed positive correlation between ERH and ataxia telangiectasia and Rad3 related (ATR) expression in liver tissues. Expression of ERH, ATR as well as checkpoint kinase 1 (CHK1) were higher in HCCs than in normal liver tissues. Knocking-down ERH augmented ultraviolet light induced DNA damage in HepG2 cells. ATR protein level is reduced upon ERH depletion as a result of defect in the splicing of ATR mRNA. Consequently, the ATR effector kinase Chk1 failed to be phosphorylated upon ultraviolet light or hydroxyurea treatment in ERH knocked-down HepG2 cells. Finally, we observed Chk1 inhibitor AZD7762 enhanced the effect of doxorubicin on inhibiting growth of HCC cells in vitro and in vivo. This study suggested that ERH regulates the splicing of the DNA damage response proteins ATR in HCC cells, and targeting DNA damage response by Chk1 inhibitor augments chemotherapy to treat HCC cells.
authors.affiliation: 1] Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan [2] Far-Eastern Memorial Hospital, New Taipei 220, Taiwan.
authors.forename: Meng-Tzu
authors.initials: MT
authors.lastname: Weng
authors.affiliation: Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan.
authors.forename: Tzu-Hsun
authors.initials: TH
authors.lastname: Tung
authors.affiliation: Clinical Trial Center, Taipei 100, Taiwan.
authors.forename: Jih-Hsiang
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
authors.forename: Hang-Li
authors.initials: HL
authors.lastname: Lin
authors.affiliation: Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
authors.forename: Jau-Min
authors.initials: JM
authors.lastname: Wong
authors.affiliation: Cancer Systems Biology Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH Bethesda, MD 20892, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
authors.forename: Jin-Chuan
authors.initials: JC
authors.lastname: Sheu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C484495:ERH protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse