RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma

Geeta Lal; Lakshmi Padmanabha; Brian J Smith; Rachael M Nicholson; James R Howe; M Sue O'Dorisio; Frederick E Domann Jr

doi:10.1002/cncr.22325

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RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma

Journal article

Open access

Peer reviewed

RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma

Geeta Lal, Lakshmi Padmanabha, Brian J Smith, Rachael M Nicholson, James R Howe, M Sue O'Dorisio and Frederick E Domann Jr

Cancer, Vol.107(12), pp.2752-2759

12/15/2006

DOI: 10.1002/cncr.22325

PMID: 17103461

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Abstract

Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation. RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR. The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P = .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P = .001). RIZ1 mRNA expression was significantly higher (P = .02) in unmethylated (1.22 +/- 1.2, mean +/- standard deviation [SD]), compared with methylated tissues (0.37 +/- 0.42, mean +/- SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies.

DNA-Binding Proteins - physiology

Transcription Factors - physiology

Histone-Lysine N-Methyltransferase

Humans

RNA, Messenger - analysis

Transcription Factors - genetics

DNA-Binding Proteins - genetics

Promoter Regions, Genetic - drug effects

RNA, Messenger - metabolism

Azacitidine - pharmacology

Thyroid Neoplasms - genetics

DNA Methylation

Cell Line, Tumor

Antimetabolites, Antineoplastic - pharmacology

Carcinoma - genetics

Epigenesis, Genetic - drug effects

Nuclear Proteins - physiology

Gene Expression Regulation, Neoplastic - drug effects

Nuclear Proteins - genetics

Details

Title: Subtitle: RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma
Creators: Geeta Lal - Department of Surgery, Division of Surgical Oncology, University of Iowa, Iowa City, Iowa, USA
Lakshmi Padmanabha
Brian J Smith
Rachael M Nicholson
James R Howe
M Sue O'Dorisio
Frederick E Domann Jr
Resource Type: Journal article
Publication Details: Cancer, Vol.107(12), pp.2752-2759
DOI: 10.1002/cncr.22325
PMID: 17103461
NLM abbreviation: Cancer
ISSN: 0008-543X
eISSN: 1097-0142
Publisher: United States
Grant note: R21 CA 91578 / NCI NIH HHS R01 CA73612 / NCI NIH HHS R01 CA82691 / NCI NIH HHS
Language: English
Date published: 12/15/2006
Academic Unit: Stead Family Department of Pediatrics; Pathology; Biostatistics; Surgery; Radiation Oncology; Holden Comprehensive Cancer Center
Record Identifier: 9983997442902771

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