Novel tumor-suppressor gene epidermal growth factor-containing fibulin-like extracellular matrix protein 1 is epigenetically silenced and associated with invasion and metastasis in human gastric cancer.
The present study aimed to investigate the role of histone modification and DNA methylation in epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) silencing in gastric cancer (GC). In the present study, four GC cell lines, and 45 paired normal and GC tissue samples were used to assess EFEMP1 expression using quantitative polymerase chain reaction (PCR), and EFEMP1 gene methylation status was evaluated by methylation-specific PCR. The involvement of histone modification in GC cell lines was examined by a chromatin immunoprecipitation (ChIP) assay. The results demonstrated that EFEMP1 mRNA level and methylation status in the EFEMP1 promoter region was associated with tumor differentiation, depth of tumor invasion and lymph node metastasis. DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) rapidly reduced DNA methylation and histone H3-K9 trimethylation at the silenced loci and reactivated EFEMP1 expression. By contrast, the histone deacetylase inhibitor trichostatin A markedly increased histone H3-K9 acetylation. However, it had no effect on DNA methylation, histone H3-K9 trimethylation or gene expression. In conclusion, the results suggested that EFEMP1 may function as a tumor suppressor in GC. Aberrant DNA methylation and histone H3-K9 trimethylation of EFEMP1 may be responsible for its downregulation in GC, and thus have an important role in tumor invasion and metastasis.
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, P.R. China.
Xin-Jiang
XJ
Zhu
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, P.R. China.
Jian
J
Liu
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, P.R. China.
Xiao-Yang
XY
Xu
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, P.R. China.
Chun-Dong
CD
Zhang
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning 110032, P.R. China.
Dong-Qiu
DQ
Dai
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*
C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A