Wnt/β-catenin signaling induces the transcription of cystathionine-γ-lyase, a stimulator of tumor in colon cancer
Wnt/β-catenin signaling induces the transcription of cystathionine-γ-lyase, a stimulator of tumor in colon cancer
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Wnt/β-连环蛋白信号传导诱导胱硫醚-γ-裂解酶的转录，胱硫醚-γ-裂解酶是结肠癌中的肿瘤刺激物
DOI：
10.1016/j.cellsig.2014.08.023
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发表时间：
2014-12-01
影响因子：
4.8
通讯作者：
Zha, Xiliang
中科院分区：
文献类型：
--
作者：
Fan, Kun;Li, Na;Zha, Xiliang
胱硫醚-γ-半胱氨酸酶(CSE)是产生H_2S的主要内源酶，作为第三种气体递质，在许多生理和病理过程中发挥着重要作用。CSE基因表达的调控机制尚不清楚，CSE/H_2S在肿瘤尤其是结肠癌中的作用也没有得到深入的认识。我们的研究表明，CSE基因的表达受Wnt途径在转录水平上的调控。Wnt3a或LiCl激活Wnt通路可增加CSE的mRNA和蛋白水平，而siRNA介导的沉默β-catenin可降低CSE的mRNA和蛋白水平。XAV939处理加速了β-连环蛋白的降解，降低了CSE蛋白水平。为了揭示这一机制，在CSE启动子中发现了两个TCF/LEF结合位点，其活性对293T细胞中β-连环素的过度表达具有正反应。Tcf/Lef结合位点突变导致启动子活性增加。这表明Tcf/Lef可能是CSE基因转录的抑制因子，而Wnt信号参与了β-连环素的自由积累，从而可能缓解了这种抑制。无论是shRNA(ShCSE)敲除CSE还是PAG抑制CSE，都会减少SW480细胞的增殖、迁移和裸鼠移植瘤的生长。综上所述，我们证明了Wnt途径在转录水平上调控CSE基因的表达，CSE/H2S在结肠癌中起重要作用。(C)2014 Elsevier Inc.保留所有权利。
Cystathionine-gamma-Iyase (CSE) is a major endogenous enzyme producing H2S which, as a third gasotransmitter, plays important roles in many physiological and pathological processes. The mechanism of regulating CSE gene expression is unclear and the roles of CSE/H2S in tumor also have not got a profound understanding, especially in colon cancer. Our study demonstrated that CSE gene expression was regulated by the Wnt pathway on transcriptional level. Activating the Wnt pathway by either Wnt3a or LiCl increased CSE mRNA and protein levels, while siRNA-mediated silence of beta-catenin decreased CSE mRNA and protein levels. XAV939 treatment which accelerated beta-catenin degradation could reduce CSE protein level. To reveal the mechanism, two TCF/LEF binding sites were found in CSE promoter whose activity had a positive response to beta-catenin overexpression in 293 T cells. Mutations of TCF/LEF binding sites led to an increase of the promoter activity. It indicated that TCF/LEF likely acted as a repressor to CSE gene transcription, and Wnt signal contributed to free beta-catenin accumulation to possibly relieve the repression. Either knockdown of CSE by shRNA (shCSE) or its inhibition by PAG decreased SW480 cell proliferation, migration, and tumor xenograft growth in nude mice. In conclusion, we have demonstrated that the Wnt pathway regulates CSE gene expression on transcriptional level and CSE/H2S plays important roles in colon cancer. (C) 2014 Elsevier Inc. All rights reserved.