Affiliations of authors: Y. Tokumaru, S. Nomoto, K. Yamashita, D. Sidransky, Department of OtolaryngologyHead and Neck Surgery, Head and Neck Cancer Research Division, The Johns Hopkins University School of Medicine, Baltimore, MD; D.-I. Sun, Department of Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul.
Correspondence to: David Sidransky, M.D., Head and Neck Cancer Research, The Johns Hopkins University School of Medicine, 818 Ross Research Bldg., 720 Rutland Ave., Baltimore, MD 212052196 (e-mail: dsidrans{at}jhmi.edu).
Jing et al. (1), by using a selective subtractive differential gene display, identified a gene whose decreased expression may contribute to the growth and expression of prostate cancer. They found that this gene was identical to tazarotene-induced gene 1 (TIG1), located on chromosomal arm 3p, and that it encoded a protein of 228 amino acids. Expression of TIG1 was completely abrogated in 92.2% of prostate carcinomas, and restoration of TIG1 expression resulted in a large reduction in both the ability of prostate cancer cells to invade extracellular matrix and the average weight of subcutaneous tumors in nude mice (1). In an accompanying editorial, Lotan (2) suggested that epigenetic mechanisms of transcriptional silencing such as hypermethylation might play an important role in the loss of TIG1 function in cancer.
To test this hypothesis, we first evaluated the methylation status of TIG1 in cancer cell lines by methylation-specific polymerase chain reaction (MSP) (3). MSP revealed that the TIG1 promoter was methylated in three of four prostate, five of five head and neck, two of six lung, and none of three bladder cancer cell lines (Table 1). To confirm the MSP results, we isolated genomic DNA from all MSP-positive cell lines, treated the DNA with bisulfite, and then directly sequenced the dense CpG regions. We found that the promoter regions contained methylated cytosines.
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We then used MSP to check the methylation status of TIG1 in primary prostate cancers (n = 31), head and neck cancers (n = 32), and lung cancers (n = 30). MSP revealed TIG1 methylation in 17 (54.8%) prostate cancers, 16 (50.0%) head and neck cancers, and 13 (43.3%) of lung cancers (Table 1). We extracted DNA from 14 prostate biopsy samples from individuals with no evidence of malignancy and 11 oral epithelium samples from healthy nonsmokers. MSP revealed no TIG1 methylation in any normal sample (Table 1
). We thus observed a cancer-specific pattern of TIG1 methylation in approximately 50% of primary prostate, head and neck, and lung cancers.
As first suggested by Lotan (2), our results support the notion that promoter methylation is an important mechanism of TIG1 gene inactivation and occurs frequently in major human tumors. Moreover, TIG1 methylation represents a new molecular marker for targeted diagnostic and therapeutic approaches in these cancers.
NOTES
Editors note: Dr. Lotan declined to respond to the correspondence.
Funding for the study described in this article was provided by Virco, Inc. Under a licensing agreement between The Johns Hopkins University and Virco, Dr. Sidransky is entitled to a share of royalty received by the University on sales or products described in this article. The University and Dr. Sidransky own Virco stock, which is subject to certain restrictions under University policy. Dr. Sidransky is a paid consultant to Virco. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
REFERENCES
1 Jing C, El-Ghany MA, Beesley C, Foster CS, Rudland PS, Smith P, et al. Tazarotene-induced gene 1 (TIG1) expression in prostate carcinomas and its relationship to tumorigenicity. J Natl Cancer Inst 2002;94:48290.
2 Lotan R. Is TIG1 a new tumor suppressor in prostate cancer? J Natl Cancer Inst 2002;94:46970.
3 Rosas SL, Koch W, da Costa Carvalho MG, Wu L, Califano J, Westra W, et al. Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res 2001;61:93942.
4 Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002;31:1419.[CrossRef][ISI][Medline]
5 Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 2003;3:8995.[ISI][Medline]
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