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Article: Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis

TitleCarbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis
Authors
KeywordsColorectal cancer genes
Gene regulation
molecular carcinogenesis
tumour markers
Issue Date2016
Citation
Gut, 2016, v. 65, n. 9, p. 1482-1493 How to Cite?
AbstractObjective We found that carbonic anhydrase IV (CA4), a member of the carbonic anhydrases, is silenced in colorectal cancer (CRC). We analysed its epigenetic inactivation, biological effects and prognostic significance in CRC. Design The biological functions of CA4 were determined by in vitro and in vivo tumorigenicity assays. The CA4 co-operator was identified by immunoprecipitation and mass spectrometry. CA4 downstream effectors and signalling pathways were elucidated by promoter luciferase assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. The clinical impact of CA4 was assessed in 115 patients with CRC. Results CA4 was silenced in all nine CRC cell lines and 92.6% of CRC tumours. The promoter hypermethylation contributed to the inactivation of CA4, and it was detected in 75.7% of the patients with CRC. After a median follow-up of 49.3 months, multivariate analysis showed that the patients with CA4 hypermethylation had a recurrence of Stage II/III CRC. The re-expression of CA4 inhibited cell proliferation, induced apoptosis and cell cycle arrest in the G1 phase. CA4 inhibited the activity of the Wnt signalling pathway and mediated the degradation of β-catenin. CA4 interacted with Wilms' tumour 1-associating protein (WTAP) and induced WTAP protein degradation through polyubiquitination. Moreover, CA4 promoted the transcriptional activity of Wilms' tumour 1 (WT1), an antagonist of the Wnt pathway, which resulted in the induction of transducin β-like protein 1 (TBL1) and the degradation of β-catenin. Conclusions CA4 is a novel tumour suppressor in CRC through the inhibition of the Wnt signalling pathway by targeting the WTAP-WT1-TBL1 axis. CA4 methylation may serve as an independent biomarker for the recurrence of CRC.
Persistent Identifierhttp://hdl.handle.net/10722/336138
ISSN
2023 Impact Factor: 23.0
2023 SCImago Journal Rankings: 8.052
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, Jingwan-
dc.contributor.authorTsoi, Ho-
dc.contributor.authorLi, Xiaoxing-
dc.contributor.authorWang, Hua-
dc.contributor.authorGao, Jing-
dc.contributor.authorWang, Kunning-
dc.contributor.authorGo, Minnie Yy-
dc.contributor.authorNg, Siew C.-
dc.contributor.authorChan, Francis Kl-
dc.contributor.authorSung, Joseph Jy-
dc.contributor.authorYu, Jun-
dc.date.accessioned2024-01-15T08:23:49Z-
dc.date.available2024-01-15T08:23:49Z-
dc.date.issued2016-
dc.identifier.citationGut, 2016, v. 65, n. 9, p. 1482-1493-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/336138-
dc.description.abstractObjective We found that carbonic anhydrase IV (CA4), a member of the carbonic anhydrases, is silenced in colorectal cancer (CRC). We analysed its epigenetic inactivation, biological effects and prognostic significance in CRC. Design The biological functions of CA4 were determined by in vitro and in vivo tumorigenicity assays. The CA4 co-operator was identified by immunoprecipitation and mass spectrometry. CA4 downstream effectors and signalling pathways were elucidated by promoter luciferase assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. The clinical impact of CA4 was assessed in 115 patients with CRC. Results CA4 was silenced in all nine CRC cell lines and 92.6% of CRC tumours. The promoter hypermethylation contributed to the inactivation of CA4, and it was detected in 75.7% of the patients with CRC. After a median follow-up of 49.3 months, multivariate analysis showed that the patients with CA4 hypermethylation had a recurrence of Stage II/III CRC. The re-expression of CA4 inhibited cell proliferation, induced apoptosis and cell cycle arrest in the G1 phase. CA4 inhibited the activity of the Wnt signalling pathway and mediated the degradation of β-catenin. CA4 interacted with Wilms' tumour 1-associating protein (WTAP) and induced WTAP protein degradation through polyubiquitination. Moreover, CA4 promoted the transcriptional activity of Wilms' tumour 1 (WT1), an antagonist of the Wnt pathway, which resulted in the induction of transducin β-like protein 1 (TBL1) and the degradation of β-catenin. Conclusions CA4 is a novel tumour suppressor in CRC through the inhibition of the Wnt signalling pathway by targeting the WTAP-WT1-TBL1 axis. CA4 methylation may serve as an independent biomarker for the recurrence of CRC.-
dc.languageeng-
dc.relation.ispartofGut-
dc.subjectColorectal cancer genes-
dc.subjectGene regulation-
dc.subjectmolecular carcinogenesis-
dc.subjecttumour markers-
dc.titleCarbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1136/gutjnl-2014-308614-
dc.identifier.pmid26071132-
dc.identifier.scopuseid_2-s2.0-84931303742-
dc.identifier.volume65-
dc.identifier.issue9-
dc.identifier.spage1482-
dc.identifier.epage1493-
dc.identifier.eissn1468-3288-
dc.identifier.isiWOS:000381274700013-

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