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5-Aza-2′-deoxycytidine leads to down-regulation of aberrant p16INK4A RNA transcripts and restores the functional retinoblastoma protein pathway in hepatocellular carcinoma cell lines

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Author(s)
Seong-Il SuhHo-Young PyunJae-We ChoWon-Ki BaekJae-Bok ParkTaeg Kyu KwonJong-Wook ParkMin-Ho SuhDennis A. Carson
Keimyung Author(s)
Suh, Seong IlBaek, Won KiSuh, Min HoKwon, Taeg KyuPark, Jong Wook
Department
Dept. of Microbiology (미생물학)
Dept. of Immunology (면역학)
Institute for Medical Science (의과학연구소)
Journal Title
Cancer Letters
Issued Date
2000
Volume
160
Issue
1
Abstract
The inactivation of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor p16INK4A may be caused by gene deletion, mutation or promoter hypermethylation. We have previously reported that p16INK4A in hepatocellular carcinoma (HCC) tissues and cell lines is inactivated predominantly by promoter hypermethylation rather than genomic aberrations. In the present experiments, we have studied the effects of the demethylating agent, 5-aza-2′-deoxycytidine (5-AZA/decitabine), on the expression of aberrant p16INK4A RNA transcripts and the CDK–retinoblastoma gene pathway in HCC cell lines with p16INK4A promoter hypermethylation. The expression of aberrant p16INK4A RNA transcripts was down-regulated and p16INK4A protein was strongly re-expressed in the HCC cell lines, SNU 354, 398, 423 and 475 after 5-AZA/decitabine treatment for 5 days. The re-expressed p16INK4A was functional, because it bound to and inhibited CDK4 kinase activity, and increased the concentrations of the hypophosphorylated form of retinoblastoma protein (pRB) in cells with a wild type RB gene. Moreover, treatment with the demethylating agent led not only to G1 cell cycle arrest, but also to the increased expression of the senescence-associated marker β-galactosidase. This up-regulation of p16INK4A mRNA and protein correlated with demethylation of the p16INK4A promoter, and with the down-regulation or disappearance of aberrant p16INK4A transcripts. These results suggest that the aberrant p16INK4A RNA transcript can be transcribed from the methylated p16INK4A gene, and endogenous reactivation of functional p16INK4A mRNA by a demethylating agent can restore the pRB pathway in HCC, and foster the terminal differentiation of the malignant cells. Therefore, demethylating agents, such as 5-AZA/decitabine, may have potential in the treatment of HCC.

Keywords
p16INK4A;
Methylation;
Aberrant RNA transcription;
Cyclin-dependent kinase–retinoblastoma protein pathway
Keimyung Author(s)(Kor)
서성일
백원기
서민호
권택규
박종욱
Publisher
School of Medicine
Citation
Seong-Il Suh et al. (2000). 5-Aza-2′-deoxycytidine leads to down-regulation of aberrant p16INK4A RNA transcripts and restores the functional retinoblastoma protein pathway in hepatocellular carcinoma cell lines. Cancer Letters, 160(1), 81–88. doi: 10.1016/S0304-3835(00)00566-8
Type
Article
ISSN
0304-3835
Source
http://lps3.www.sciencedirect.com.proxy.dsmc.or.kr/science/article/pii/S0304383500005668?via%3Dihub
DOI
10.1016/S0304-3835(00)00566-8
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35317
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Microbiology (미생물학)
3. Research Institutues (연구소) > Institute for Medical Science (의과학연구소)
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