Zinc-Finger Protein 471 Functions as a Tumor Suppressor in Gastric Cancer through Transcriptionally Repressing TFAP2A and PLS3
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AbstractBackgrounds & Aims: Zinc-finger protein 471 (ZNF471), a transcription factor, was found to be preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. The present study aims to elucidate the functional role, molecular mechanisms and clinical impact of ZNF471 in gastric cancer.Methods: ZNF471 methylation status was evaluated by bisulfite genomic sequencing (BGS). The biological function of ZNF471 was determined by cell proliferation, apoptosis, migration and invasion assays. The downstream binding targets of ZNF471 was predicted with bioinfor- matics model and confirmed by ChIP-PCR. The clinical impact of ZNF471 was assessed in 121 gastric cancer patients. Results: ZNF471 mRNA expression was silenced or downregulated in 16 out of 17 gastric cancer cell lines. The ZNF471 mRNA expression was markedly reduced in 75 gastric cancer tissues compared with their adjacent normal tissues (P<0.01). We further revealed that silence or downregulation of ZNF471 was mediated by its promoter hypermethylation as determined by BGS. Significantly higher promotor methylation level was observed in gastric cancer tissues than their adjacent normal (P<0.001). A negative association between ZNF471 promoter methylation and mRNA expression was demonstrated (R=-0.596, P=0.0013; n=26). This negative association was validated in TCGA data (R=- 0.35, P=4.3e-11; n=398). In addition, ZNF471 promotor hypermethylation was associated with poor survival of gastric cancer patients (n=121, P<0.05). Ectopic expression of ZNF471 in gastric cancer cell lines AGS and BGC823 significantly suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis, whereas knockdown of ZNF471 in gastric cancer cell line MKN1 and normal gastric epithelial cell line GES1 displayed tumor- promoting effects. In addition, overexpression of ZNF471 in BGC823 cell line significantly inhibited the tumorigenesis in nude mice compared to controls. We further demonstrated that plastin 3 (PLS3) and transcription factor AP-2 Alpha (TFAP2A) are two downstream transcriptional targets of ZNF471 using the integrative analyses of predicted binding motif and ENCODE data base. ChIP-PCR confirmed the direct binding of ZNF471 in the promoters of PLS3 and TFAP2A in AGS and BGC823 cells. Moreover, ZNF471 transfection in AGS and BGC823 cells significantly inhibited the mRNA expression of PLS3 and TFAP2A. The functional investigation revealed that both PLS3 and TFAP2A played oncogenic effects in gastric cancer. Conclusion: ZNF471 is a critical tumor suppressor in gastric cancer through directly inhibiting oncogenic factors PLS3 and TFAP2A.
All Author(s) ListLei Cao, Shiyan Wang, Yanquan Zhang, Ka Chun Wong, Daniel Nakatsu, Joseph J. Sung, Jun Yu
Name of ConferenceDigestive Disease Week 2017
Start Date of Conference06/05/2017
End Date of Conference09/05/2017
Place of ConferenceChicago
Country/Region of ConferenceUnited States of America
Volume Number152
Issue Number5, Suppl. 1
PagesS801 - S802
LanguagesEnglish-United States

Last updated on 2022-11-01 at 23:30