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J Biol Chem. 2017 Feb 10;292(6):2143-2158. doi: 10.1074/jbc.M116.770727. Epub 2016 Dec 27.

RYBP Expression Is Regulated by KLF4 and Sp1 and Is Related to Hepatocellular Carcinoma Prognosis.

Author information

1
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.
2
the Department of Hepatobiliary Surgery, Nantong Third Hospital, Nantong University, Nantong, Jiangsu 226006, China, and.
3
the Department of Clinical Laboratory Medicine, Nantong Maternal and Child Health Hospital, Nantong, Jiangsu 226018, China.
4
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.
5
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.

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 human RYBP gene. 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 of RYBP to induce and suppress RYBP transcription, respectively. We mapped the binding sites of KLF4 and Sp1 on the RYBP promoter. Studies in vitro showed that KLF4 suppresses whereas Sp1 promotes HCC cell growth through modulating RYBP expression. Deregulated KLF4 and Sp1 contributed to decreased expression of RYBP in 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.

KEYWORDS:

Kruppel-like factor 4 (KLF4); RYBP; gene expression; gene regulation; hepatocellular carcinoma; promoter; specificity protein 1 (Sp1)

PMID:
28028181
PMCID:
PMC5313089
DOI:
10.1074/jbc.M116.770727
[Indexed for MEDLINE]
Free PMC Article

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