Enhancer of rudimentary homolog regulates DNA damage response in hepatocellular carcinoma

Meng-Tzu Weng; Tzu-Hsun Tung; Jih-Hsiang Lee; Shu-Chen Wei; Hang-Li Lin; Yu-Jung Huang; Jau-Min Wong; Ji Luo; Jin-Chuan Sheu

doi:10.1038/srep09357

Enhancer of rudimentary homolog regulates DNA damage response in hepatocellular carcinoma

Sci Rep. 2015 Apr 9:5:9357. doi: 10.1038/srep09357.

Authors

Meng-Tzu Weng¹, Tzu-Hsun Tung², Jih-Hsiang Lee³, Shu-Chen Wei⁴, Hang-Li Lin⁴, Yu-Jung Huang², Jau-Min Wong⁴, Ji Luo⁵, Jin-Chuan Sheu⁴

Affiliations

¹ 1] Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan [2] Far-Eastern Memorial Hospital, New Taipei 220, Taiwan.
² Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan.
³ Clinical Trial Center, Taipei 100, Taiwan.
⁴ Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan.
⁵ Cancer Systems Biology Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH Bethesda, MD 20892, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibiotics, Antineoplastic / pharmacology
Antibiotics, Antineoplastic / therapeutic use
Antibiotics, Antineoplastic / toxicity
Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Proliferation / drug effects
Checkpoint Kinase 1
DNA Damage* / radiation effects
DNA Repair*
Drug Synergism
Hep G2 Cells
Humans
Liver / metabolism
Liver Neoplasms / drug therapy
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Kinases / chemistry
Protein Kinases / metabolism
RNA Interference
RNA, Messenger / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism*
Ultraviolet Rays

Substances

Antibiotics, Antineoplastic
Cell Cycle Proteins
ERH protein, human
RNA, Messenger
Transcription Factors
Protein Kinases
Ataxia Telangiectasia Mutated Proteins
CHEK1 protein, human
Checkpoint Kinase 1
Chek1 protein, mouse