title: Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer.
abstract: Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at -167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Department of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210029, China.
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Lilin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
mesh_terms: D000368:Aged; D000818:Animals; D023102:Anoikis / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D054875:Ubiquitination; D015854:Up-Regulation / Q000235:genetics*; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D047490:Retinoid X Receptor alpha; C509761:SPOP protein, human; D000075746:Zinc Finger Protein Gli2