title: Sp1 is involved in regulation of cystathionine γ-lyase gene expression and biological function by PI3K/Akt pathway in human hepatocellular carcinoma cell lines.
abstract: Hydrogen sulfide (H(2)S) has been found to play an important role as a novel gasotransmitter involved in many biological processes. The regulatory role of endogenous H(2)S-producing enzyme on cancer cell survival is complex and unclear. According to the data that cystathionine γ-lyase (CSE) gene, catalyzed H(2)S production in trans-sulfuration pathway, was upregulated in Akt stably transformed mouse embryonic fibroblast cells, the mechanisms that elevated CSE expression by PI3K/Akt signaling pathway and its biological functions in cell survival were studied. In the present study, firstly, the results showed that PI3K/Akt positively correlated with CSE expression levels in human hepatocellular carcinoma cell lines. CSE expression was decreased by the PI3K inhibitor or Akt deletion, while upregulated with the activating of Akt. Based on dual-luciferase reporter assay, the -592/+139 gene fragment represented the CSE core promoter, and the PI3K/Akt pathway regulated CSE expression on transcriptional level. Sp1 was the critical transcription factor in regulation of CSE expression via the mutation of transcription factor binding sites on the promoter. Furthermore, we proved that Sp1 could directly bind to CSE promoter by ChIP assay. In addition, we explored that the endogenous H(2)S production was connected with the regulated CSE expression, and CSE/H(2)S promoted human hepatocellular carcinoma cell proliferation via cell cycle progression regulation. In summary, we have, for the first time, demonstrated that PI3K/Akt pathway regulates the CSE expression via Sp1, which is particularly important to understand the effect of PI3K/Akt and CSE on the tumorigenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yin
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Zengxia
authors.initials: Z
authors.lastname: Li
authors.forename: Chuanzhong
authors.initials: C
authors.lastname: Mei
authors.forename: Wantong
authors.initials: W
authors.lastname: Yao
authors.forename: Yonglei
authors.initials: Y
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qi
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Shi
authors.forename: Shuangjian
authors.initials: S
authors.lastname: Qiu
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Xiliang
authors.initials: X
authors.lastname: Zha
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003542:Cystathionine gamma-Lyase / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013447:Sulfites / Q000378:metabolism
chemical_list: D016329:Sp1 Transcription Factor; D013447:Sulfites; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003542:Cystathionine gamma-Lyase; C042345:hydrogen sulfite