Discovery of Epigenetically Masked Tumor Suppressor Genes in Endometrial Cancer
Open Access
- 1 May 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 3 (5) , 261-269
- https://doi.org/10.1158/1541-7786.mcr-04-0110
Abstract
Realization that many tumor suppressor genes are silenced by epigenetic mechanisms has stimulated the discovery of novel tumor suppressor genes. We used a variety of research tools to search for genes that are epigenetically silenced in human endometrial cancers. Changes in global gene expression of the endometrial cancer cell line Ishikawa was analyzed after treatment with the demethylating agent 5-aza-2′-deoxycytidine combined with the histone deacetylase inhibitor suberoylanilide bishydroxamide. By screening over 22,000 genes, candidate tumor suppressor genes were identified. Additional microarray analysis and real-time reverse transcription-PCR of normal and cancerous endometrial samples and search for CpG islands further refined the list. Tazarotene-induced gene-1 (Tig1) and CCAAT/enhancer binding protein-α (C/ebpα) were chosen for further study. Expression of both genes was low in endometrial cancer cell lines and clinical samples but high in normal endometrial tissues. Bisulfite sequencing, restriction analysis, and/or methylation-specific PCR revealed aberrant methylation of the CpG island in the Tig1 gene of all 6 endometrial cancer cell lines examined and 4 of 18 clinical endometrial cancers, whereas the C/ebpα promoter remained unmethylated in endometrial cancers. Chromatin immunoprecipitation showed increased acetylated histone H3 bound to both Tig1 and C/ebpα genes after treatment with 5-aza-2′-deoxycytidine and/or suberoylanilide bishydroxamide. Forced expression of either TIG1 or C/EBPα led to significant growth reduction of Ishikawa cells. Our data suggest that C/ebpα and Tig1 function as tumor suppressor proteins in endometrial cancers and that their reexpression may be a therapeutic target.Keywords
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