title: RYBP Expression Is Regulated by KLF4 and Sp1 and Is Related to Hepatocellular Carcinoma Prognosis.
abstract: The expression of Ring1- and YY1-binding protein (RYBP) is reduced in several human cancers, but the molecular mechanism(s) have remained elusive. In this study, we used human hepatocellular carcinoma (HCC) cell lines and tissue specimens to study the mechanism and herein report several new findings. First, we cloned and characterized the basal promoter region of the humanRYBPgene. We found that the decreased RYBP expression in HCC tissues was not due to promoter sequence variation/polymorphisms or CpG dinucleotide methylation. We identified two transcription factors, KLF4 and Sp1, which directly bind the promoter region ofRYBPto induce and suppressRYBPtranscription, respectively. We mapped the binding sites of KLF4 and Sp1 on theRYBPpromoter. Studiesin vitroshowed that KLF4 suppresses whereas Sp1 promotes HCC cell growth through modulating RYBP expression. Deregulated KLF4 and Sp1 contributed to decreased expression ofRYBPin HCC tumor tissues. Our studies of human HCC tissues indicated that a diminished RYBP level in the tumor (in association with altered KLF4 and Sp1 expression) was statistically associated with a larger tumor size, poorer differentiation, and an increased susceptibility to distant metastasis. These findings help to clarify why RYBP is decreased in HCC and indicate that deregulated KLF4, Sp1, and RYBP may lead to a poorer prognosis. Our findings support the idea that RYBP may represent a target for cancer therapy and suggest that it may be useful as a prognostic biomarker for HCC, either alone or in combination with KLF4 and Sp1.
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Qiaojiajie
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: the Department of Hepatobiliary Surgery, Nantong Third Hospital, Nantong University, Nantong, Jiangsu 226006, China, and.
authors.forename: Weihua
authors.initials: W
authors.lastname: Cai
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Tian
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Junwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: the Department of Clinical Laboratory Medicine, Nantong Maternal and Child Health Hospital, Nantong, Jiangsu 226018, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Hou
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China, hbr541@hotmail.com.
authors.forename: Bingren
authors.initials: B
authors.lastname: Huang
authors.affiliation: From the State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China, chendeng2001@hotmail.com.
authors.forename: Deng
authors.initials: D
authors.lastname: Chen
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D005822:Genetic Vectors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C434957:RYBP protein, human; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor
keywords: Kruppel-like factor 4 (KLF4); RYBP; gene expression; gene regulation; hepatocellular carcinoma; promoter; specificity protein 1 (Sp1)