This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takai, N. Articles by Koeffler, H. P. Search for Related Content PubMed PubMed Citation Articles by Takai, N. Articles by Koeffler, H. P.

---

Cancer Genes and Genomics

Discovery of Epigenetically Masked Tumor Suppressor Genes in Endometrial Cancer

¹ Division of Hematology/Oncology and ² Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center and ³ Department of Pathology, Center of Health Science, University of California at Los Angeles School of Medicine; ⁴ Department of Biochemistry, School of Medicine, University of Southern California, Los Angeles, CA and ⁵ Department of Obstetrics and Gynecology, Oita University Faculty of Medicine, Oita, Japan

Requests for reprints: Norihiko Kawamata, Division of Hematology/Oncology, Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7736; Fax: 310-423-0443. E-mail: kawamatan{at}cshs.org

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- (C/ebp) 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/ebp promoter remained unmethylated in endometrial cancers. Chromatin immunoprecipitation showed increased acetylated histone H3 bound to both Tig1 and C/ebp genes after treatment with 5-aza-2'-deoxycytidine and/or suberoylanilide bishydroxamide. Forced expression of either TIG1 or C/EBP led to significant growth reduction of Ishikawa cells. Our data suggest that C/ebp and Tig1 function as tumor suppressor proteins in endometrial cancers and that their reexpression may be a therapeutic target.

This article has been cited by other articles:

				K. D. Loomis, S. Zhu, K. Yoon, P. F. Johnson, and R. C. Smart Genetic Ablation of CCAAT/Enhancer Binding Protein {alpha} in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis Cancer Res., July 15, 2007; 67(14): 6768 - 6776. [Abstract] [Full Text] [PDF]

				R. Vibhakar, G. Foltz, J.-g. Yoon, L. Field, H. Lee, G.-y. Ryu, J. Pierson, B. Davidson, and A. Madan Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma Neuro-oncol, April 1, 2007; 9(2): 135 - 144. [Abstract] [Full Text] [PDF]

				J. L. Hecht and G. L. Mutter Molecular and Pathologic Aspects of Endometrial Carcinogenesis J. Clin. Oncol., October 10, 2006; 24(29): 4783 - 4791. [Abstract] [Full Text] [PDF]

				G. Foltz, G.-Y. Ryu, J.-G. Yoon, T. Nelson, J. Fahey, A. Frakes, H. Lee, L. Field, K. Zander, Z. Sibenaller, et al. Genome-Wide Analysis of Epigenetic Silencing Identifies BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma. Cancer Res., July 1, 2006; 66(13): 6665 - 6674. [Abstract] [Full Text] [PDF]

				D. S. Basseres, E. Levantini, H. Ji, S. Monti, S. Elf, T. Dayaram, M. Fenyus, O. Kocher, T. Golub, K.-k. Wong, et al. Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBP{alpha} in Mice Mol. Cell. Biol., February 1, 2006; 26(3): 1109 - 1123. [Abstract] [Full Text] [PDF]