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  • Oncogenomics
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Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

Abstract

Methylation of CpG islands and associated gene silencing may lead to malignant progression, but the mechanisms of CpG island methylation in cancer are unknown. The tazarotene-induced gene 1 (TIG1), also known as retinoid acid (RA) receptor-responsive 1 gene was first identified as an RA-responsive gene and was shown to be downregulated in prostate cancer. Here, we show that this downregulation is caused by the methylation of the promoter and CpG island of TIG1. TIG1 was methylated in 26 of 50 (52%) primary prostate cancers, but was not methylated in normal tissues or benign hyperplasias. Three of four tumors that metastasized, five of six that were poorly differentiated and all that were assigned a Gleason score higher than 8 (7/7) were methylated in the promoter of TIG1. The samples with peripheral invasion were more frequently methylated (21/32, 66%) than tissues without peripheral invasion (5/18, 28%). In addition, Gleason 7–10 cancers (21/30, 70%) were significantly more frequently methylated compared with Gleason 4–6 cancers (4/18, 22%) (P<0.01). The retinoic acid receptor beta (RAR-beta) gene was frequently methylated as well (42/50, 84%). When TIG1 showed methylation, RAR-beta was also methylated (25/26 samples). In almost all samples where RAR-beta was not methylated, TIG1 was also in an unmethylated state (14/15 samples). The methylation of TIG1 and RAR-beta was positively correlated (r=0.35; P=0.017). It is possible that the methylation of the retinoid response gene TIG1 occurred in response to the methylation and inactivation of RAR-beta. These observations may contribute to our understanding of mechanistic events leading to CpG island methylation in cancer.

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Abbreviations

TIG1 :

tazarotene-induced gene 1

RAR-beta:

retinoic acid receptor beta

ER-beta:

estrogen receptor beta

RASSF1A :

Ras association domain family 1A gene

MSP:

methylation-specific PCR

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Acknowledgements

We thank Steven Bates for culturing the cell lines and Ahmad Besaratinia for help with the statistical analysis. This study was supported by a grant from the National Institutes of Health (CA88873) to GPP.

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Correspondence to Gerd P Pfeifer.

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Zhang, J., Liu, L. & Pfeifer, G. Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene. Oncogene 23, 2241–2249 (2004). https://doi.org/10.1038/sj.onc.1207328

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