Details
- Autor(en) / Beteiligte
- Titel
- Zinc-finger protein 471 suppresses gastric cancer through transcriptionally repressing downstream oncogenic PLS3 and TFAP2A
- Ist Teil von
- Oncogene, 2018-06, Vol.37 (26), p.3601-3616
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues (P < 0.001). ZNF471 promoter CpG-site hypermethylation correlated with poor survival of gastric cancer patients (n = 120, P = 0.001). Ectopic expression of ZNF471 in gastric cancer cell lines (AGS, BGC823, and MKN74) significantly suppressed cell proliferation, migration, and invasion, while it induced apoptosis in vitro and inhibited xenograft tumorigenesis in nude mice. Transcription factor AP-2 Alpha (TFAP2A) and plastin3 (PLS3) were two crucial downstream targets of ZNF471 demonstrated by bioinformatics modeling and ChIP-PCR assays. ZNF471 directly bound to the promoter of TFAP2A and PLS3 and transcriptionally inhibited their expression. TFAP2A and PLS3 showed oncogenic functions in gastric cancer cell lines. Moreover, ZNF471 recruited KAP1 to the promoter of the target genes, thereby inducing H3K9me3 enrichment for transcriptional repression and inhibition of oncogenic TFAP2A and PLS3. In conclusion, ZNF471 acts as a tumor suppressor in gastric cancer by transcriptionally inhibiting downstream targets TFAP2A and PLS3. KAP1 is a co-repressor of ZNF471 at the promoter of the target genes. The promoter CpG-site methylation is an independent prognostic factor for overall survival of gastric cancer patients.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/s41388-018-0220-5Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6021371
- Format
- –
- Schlagworte
- Analysis, Animals, AP-2 protein, Apoptosis, Apoptosis - genetics, Bioinformatics, Cell Line, Tumor, Cell migration, Cell Movement - genetics, Cell proliferation, Cell Proliferation - genetics, CpG islands, DNA methylation, Down-Regulation - genetics, Ectopic expression, Gastric cancer, Gene expression, Gene silencing, Genes, Tumor Suppressor, Genetic aspects, HEK293 Cells, Humans, Kinases, Male, Membrane Glycoproteins - biosynthesis, Membrane Glycoproteins - genetics, Membrane Glycoproteins - metabolism, Methylation, Mice, Mice, Inbred BALB C, Mice, Nude, Microfilament Proteins - biosynthesis, Microfilament Proteins - genetics, Microfilament Proteins - metabolism, Molecular modelling, Neoplasm Invasiveness - genetics, Neoplasm Transplantation, Patients, Promoter Regions, Genetic - genetics, Protein research, Repressor Proteins - genetics, Repressor Proteins - metabolism, Risk factors, RNA Interference, RNA, Small Interfering - genetics, Stomach cancer, Stomach Neoplasms - genetics, Stomach Neoplasms - mortality, Stomach Neoplasms - pathology, Transcription Factor AP-2 - biosynthesis, Transcription Factor AP-2 - genetics, Transcription Factor AP-2 - metabolism, Transplantation, Heterologous, Tripartite Motif-Containing Protein 28 - genetics, Tripartite Motif-Containing Protein 28 - metabolism, Tumor cell lines, Tumor suppressor genes, Tumorigenesis, Xenografts, Zinc finger proteins, Zinc Fingers - genetics