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European Journal of Medical Research

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01-12-2010 | Research

DNA methylation of the RIZ1 tumor suppressor gene plays an important role in the tumorigenesis of cervical cancer

Authors: HY Cheng, Y Gao, G Lou

Published in: European Journal of Medical Research | Issue 1/2010

Abtract

Objective

The retinoblastoma protein-interacting zinc finger gene RIZ1 is a tumor suppressor gene and a member of a nuclear histone/protein methyltransferase superfamily. The purpose of the present study was to examine the expression of RIZ1 and evaluate its carcinogenesis in cervical cancer. The relationship between DNA methylation and transcriptional silencing of RIZ1 was investigated in cervical cancer.

Methods

RIZ1 expression was examined in cervical cancer cell lines and cervical tissues (12 normal and 40 cancerous) by using RT polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using methylation-specific PCR (MSP).

Results

RIZ1 expression is reduced or lost in cervical cancers, compared with normal cervical tissues (P < 0.05). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. 37.5% of carcinomas were methylated, while none of normal tissues were methylated. RIZ1 mRNA expression was significantly higher (P = 0.000) in unmethylated (0.3494 ± 0.0466, mean ± SD), compared with methylated tissues (0.1422 ± 0.1073, mean ± SD). Treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline.

Conclusions

Reduced expression of RIZ1 may play an important role in the pathogenesis and/or development of cervical cancer, and is considered to be caused in part by aberrant DNA methylation.

Yu MY, Tong JH, Chan PK, Lee TL, Chan MW, Chan AW, Lo KW, To KF: Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers. Int J Cancer 2003,105(2):204–209. 10.1002/ijc.11051PubMedCrossRef

Gokul G, Gautami B, Malathi S, Sowjanya AP, Poli UR, Jain M, Ramakrishna G, Khosla S: DNA methylation profile at the DNMT3L promoter: a potential biomarker for cervical cancer. Epigenetics 2007,2(2):80–85. 10.4161/epi.2.2.3692PubMedCentralPubMedCrossRef

Wu Y, Meng L, Wang H, Xu Q, Wang S, Wu S, Xi L, Zhao Y, Zhou J, Xu G, Lu Y, Ma D: Regulation of DNA methylation on the expression of the FHIT gene contributes to cervical carcinoma cell tumorigenesis. Oncol Rep 2006,16(3):625–629.PubMed

Jo H, Kang S, Kim JW, Kang GH, Park NH, Song YS, Park SY, Kang SB, Lee HP: Hypermethylation of the COX-2 gene is a potential prognostic marker for cervical cancer. J Obstet Gynaecol Res 2007,33(3):236–241. 10.1111/j.1447-0756.2007.00517.xPubMedCrossRef

Jeong DH, Youm MY, Kim YN, Lee KB, Sung MS, Yoon HK, Kim KT: Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with clinicopathologic characteristics. Int J Gynecol Cancer 2006,16(3):1234–1240. 10.1111/j.1525-1438.2006.00522.xPubMedCrossRef

Buyse IM, Shao G, Huang S: The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein. Proc Natl Acad Sci USA 1995, 92: 4467–4471. 10.1073/pnas.92.10.4467PubMedCentralPubMedCrossRef

Weith A, Brodeur GM, Bruns GA, Matise TC, Mischke D, Nizetic D, Seldin MF, van Roy N, Vance J: Report of the Second International Workshop on Human Chromosome 1 Mapping 1995. Cytogenet Cell Genet 1996,72(23):114–144.PubMed

Huang S, Shao G, Liu L: The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatinmediated gene expression. J Biol Chem 1998, 273: 15933–15939. 10.1074/jbc.273.26.15933PubMedCrossRef

Steele-Perkins G, Fang W, Yang XH, Yang XH, Van Gele M, Carking T, Gu J, Buyse IM, Fletcher JA, Liu J, Bronson R, Chadwick RB, de la Chapelle A, Zhang X, Speleman F, Huang S: Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear proteinmethyltransferase superfamily. Genes Dev 2001,15(17):2250–2262. 10.1101/gad.870101PubMedCentralPubMedCrossRef

10.

He L, Yu JX, Liu L, Buyse IM, Wang MS, Yang QC, Nakagawara A, Brodeur GM, Shi YE, Huang S: RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis. Cancer Res 1998,58(19):4238–4244.PubMed

11.

Jiang GL, Liu L, Buyse IM, Simon D, Huang S: Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1. Int J Cancer 1999,83(4):541–547. 10.1002/(SICI)1097-0215(19991112)83:4<541::AID-IJC17>3.0.CO;2-FPubMedCrossRef

12.

Jiang GL, Huang S: Adenovirus expressing RIZ1 in tumor suppressor gene therapy of microsatellite-unstable colorectal cancers. Cancer Res 2001,61(5):1796–1798.PubMed

13.

Lal G, Padmanabha L, Smith BJ, Nicholson RM, Howe JR, O'Dorisio MS, Domann FE Jr: RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma. Cancer 2006,107(12):2752–2759. 10.1002/cncr.22325PubMedCrossRef

14.

Kass SU, Pruss D, Wolffe AP: How does DNA methylation repress transcription? Trends Genet 1997,13(11):444–449. 10.1016/S0168-9525(97)01268-7PubMedCrossRef

15.

Razin A, Ceder H: DNA methylation and gene expression. Microbiol Rev 1991,55(3):451–458.PubMedCentralPubMed

16.

Jones PA, Laird PW: Cancer epigenetics comes of age. Nat Genet 1999,21(2):163–167. 10.1038/5947PubMedCrossRef

17.

Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res 2001,61(8):3225–3229.PubMed

18.

Oshimo Y, Oue N, Mitani Y, Mitani Y, Nakayama H, Kitadai Y, Yoshida K, Chayama K, Yasui W: Frequent epigenetic inactivation of RIZ1 by promoter hypermethylation in human gastric carcinoma. Int J Cancer 2004,110(2):212–218. 10.1002/ijc.20090PubMedCrossRef

19.

Takahashi T, Shivapurkar N, Riquelme E, Shigematsu H, Reddy J, Suzuki M, Miyajima K, Zhou X, Bekele BN, Gazdar AF, Wistuba II: Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res 2004,10(18 Pt 1):6126–6133.PubMedCrossRef

20.

Matsushita C, Yang Y, Takeuchi S, Matsushita M, Van Dongen JJ, Szczepanski T, Bartram CR, Seo H, Koeffler HP, Taguchi H: Aberrant methylation in promoter-associated CpG islands of multiple genes in relapsed childhood acute lymphoblastic leukemia. Oncol Rep 2004,12(1):97–99.PubMed

21.

Huang S: The retinoblastoma protein-interacting zinc finger gene RIZ in 1p36-linked cancers. Front Biosci 1999, 4: D528-D532. 10.2741/HuangPubMedCrossRef

22.

Du Y, Carling T, Fang W, Piao Z, Sheu JG, Huang S: Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res 2001,61(22):8094–8099.PubMed

23.

Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y, Olaru A, Wang S, Mori Y, Deacu E, Hamilton J, Kan T, Krasna MJ, Beer DG, Pepe MS, Abraham JM, Feng Z, Schmiegel W, Greenwald BD, Meltzer SJ: Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene 2005,24(25):4138–4148.PubMedCrossRef

24.

Jiang GL, Huang S: The yin-yang of PR-domain family genes in tumorigenesis. Histol Histopathol 2000,15(1):109–117.PubMed

25.

Piao Z, Fang W, Malkhosyan S, Kim H, Horii A, Perucho M, Huang S: Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability. Cancer Res 2000,60(17):4701–4704.PubMed

26.

Steele-Perkins G, Fang W, Yang XH, Van Gele M, Car-ling T, Gu J, Buyse IM, Fletcher JA, Liu J, Bronson R, Chadwick RB, de la Chapelle A, Zhang X, Speleman F, Huang S: Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev 2001,15(17):2250–2262. 10.1101/gad.870101PubMedCentralPubMedCrossRef

27.

Hasegawa Y, Matsubara A, Teishima J, Seki M, Mita K, Usui T, Oue N, Yasui W: DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer. Cancer Sci 2007,98(1):32–36. 10.1111/j.1349-7006.2006.00338.xPubMedCrossRef

Title: DNA methylation of the RIZ1 tumor suppressor gene plays an important role in the tumorigenesis of cervical cancer
Authors: HY Cheng
Y Gao
G Lou
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: European Journal of Medical Research / Issue 1/2010
Electronic ISSN: 2047-783X
DOI: https://doi.org/10.1186/2047-783X-15-1-20

At a glance: The STEP trials

Springer Medicine

DNA methylation of the RIZ1 tumor suppressor gene plays an important role in the tumorigenesis of cervical cancer

Abtract

Objective

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abtract

Objective

Methods

Results

Conclusions

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