Methylation-associated silencing of the tissue inhibitor of Metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-02, Vol.59 (4), p.798-802
• Main Authors: BACHMAN, K. E, HERMAN, J. G, CORN, P. G, MERLO, A, COSTELLO, J. F, CAVENEE, W. K, BAYLIN, S. B, GRAFF, J. R
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Kidneys; Medical sciences; Nephrology. Urinary tract diseases; Neurology; Tumors of the nervous system. Phacomatoses; Tumors of the urinary system
• ISSN: 0008-5472; 1538-7445

Tissue inhibitor of metalloproteinase-3 (TIMP-3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastasis. Loss of TIMP-3 has been related to the acquisition of tumorigenesis. Herein, we show that TIMP-3 is silenced in association with aberrant promoter-region methylation in cell lines derived from human cancers. TIMP-3 expression was restored after 5-aza-2'deoxycytidine-mediated demethylation of the TIMP-3 proximal promoter region. Genomic bisulfite sequencing revealed that TIMP-3 silencing was related to the overall density of methylation and that discrete regions within the TIMP-3 CpG island may be important for the silencing of this gene. Aberrant methylation of TIMP-3 occurred in primary cancers of the kidney, brain, colon, breast, and lung, but not in any of 41 normal tissue samples. The most frequent TIMP-3 methylation was found in renal cancers, which originate in the tissue that normally expresses the highest TIMP-3 levels. This methylation correlated with a lack of detectable TIMP-3 protein in these tumors. Together, these data show that methylation-associated inactivation of TIMP-3 is frequent in many human tumors.