Wnt/β-catenin signaling induces the transcription of cystathionine-γ-lyase, a stimulator of tumor in colon cancer

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.