title: ZNF689 suppresses apoptosis of hepatocellular carcinoma cells through the down-regulation of Bcl-2 family members.
abstract: ZNF689, a C2H2-type of zinc finger transcription factor, was suggested to play a key role in hepatocarcinogenesis. However, none of the target genes or potential roles of ZNF689 in hepatocellular carcinoma (HCC) have been elucidated. Here, we investigated the role of ZNF689 in HCC cell lines focusing on cell viability and apoptosis.We found that the knockdown of ZNF689 by its specific siRNA decreased cell viability of Huh7. Cell cycle analysis revealed that the ZNF689 knockdown increased the proportion of the sub-G1 population, accompanied by an increase of annexin V- and TUNEL-positive cells.Western blot analysis revealed that ZNF689 knockdown induced the expression of pro-apoptotic factors of Bcl-2 family, Bax, Bak and jBid. There was a correlation between the expression of ZNF689 and an anticancer drug 5-fluorouracil (5-FU) resistance of HCC cells. In vivo, ZNF689 siRNA reduced tumor viability in HepG2-bearing mice with statistical significance. Furthermore, immunohistochemical analysis demonstrated that nuclei of a significant portion of human HCC surgical specimens were positive for ZNF689. Taken together, our results indicate that ZNF689 blocks pro-apoptotic signaling by suppressing the Bak/Bax/Bid pathway, resulting in the progression of liver cancer and resistance to 5-FU. ZNF689 may be a promising chemotherapeutic target against liver cancer.
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Shigematsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; C560747:ZNF689 protein, human