Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis.
Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis.
复制标题
碳酸酐酶 IV 通过靶向 WTAP-WT1-TBL1 轴抑制 Wnt 信号通路，从而抑制结肠癌的发展。
作者：
Zhang J;Tsoi H;Li X;Wang H;Gao J;Wang K;Go MY;Ng SC;Chan FK;Sung JJ;Yu J
我们发现，碳酸酐酶IV（CA 4），碳酸酐酶的成员，是沉默的结直肠癌（CRC）。我们分析了它的表观遗传失活，生物学效应和预后意义。通过体外和体内致瘤性试验，测定CA 4的生物学功能。通过免疫沉淀和质谱鉴定CA 4协同操作者。通过启动子荧光素酶分析、电泳迁移率变动分析和染色质免疫沉淀来阐明CA 4下游效应子和信号通路。在115例CRC患者中评估了CA 4的临床影响。CA 4在所有9种CRC细胞系和92.6%的CRC肿瘤中沉默。75.7%的结直肠癌患者存在CA 4基因启动子甲基化。中位随访49.3个月后，多变量分析显示CA 4高甲基化患者有II/III期CRC复发。 CA 4的重新表达抑制细胞增殖，诱导细胞凋亡和细胞周期阻滞在G1期。CA 4抑制Wnt信号通路的活性并介导β-catenin的降解。CA 4与肾母细胞瘤1相关蛋白（WTAP）相互作用，并通过多聚泛素化诱导WTAP蛋白降解。此外，CA 4促进Wnt通路的拮抗剂Wilms'tumor 1（WT 1）的转录活性，这导致转导素β样蛋白1（TBL 1）的诱导和β-连环蛋白的降解。CA 4是CRC中的一种新型肿瘤抑制剂，通过靶向WTAP-WT 1-TBL 1轴抑制Wnt信号通路。CA 4甲基化可作为CRC复发的独立生物标志物。
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. 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. 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. 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.
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影响因子：
168.9
作者：
Cunningham, David;Atkin, Wendy;Starling, Naureen
通讯作者：
Starling, Naureen
影响因子：
3.5
作者：
Little, NA;Hastie, ND;Davies, RC
通讯作者：
Davies, RC
DOI：
10.1152/ajpregu.00735.2004
发表时间：
2005-05-01
影响因子：
2.8
作者：
Purkerson, JM;Schwartz, GJ
通讯作者：
Schwartz, GJ
影响因子：
13.3
作者：
Dengiel, Joern;Kristensen, Anders Riis;Andersen, Jens S.
通讯作者：
Andersen, Jens S.
影响因子：
14.8
作者：
Lee, Tong Ihn;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.