Abstract
BackgroundTranscriptional silencing associated with aberrant promoter methylation has been established as an alternate pathway for the development of cancer by inactivating tumor suppressor genes. TMS1 (Target of Methylation induced Silencing), also known as ASC (Apoptosis Speck like protein containing a CARD) is a tumor suppressor gene which encodes for a CARD (caspase recruitment domain) containing regulatory protein and has been shown to promote apoptosis directly and by activation of downstream caspases. This study describes the methylation induced silencing of TMS1/ASC gene in prostate cancer cell lines. We also examined the prevalence of TMS1/ASC gene methylation in prostate cancer tissue samples in an effort to correlate race and clinico-pathological features with TMS1/ASC gene methylation.ResultsLoss of TMS1/ASC gene expression associated with complete methylation of the promoter region was observed in LNCaP cells. Gene expression was restored by a demethylating agent, 5-aza-2'deoxycytidine, but not by a histone deacetylase inhibitor, Trichostatin A. Chromatin Immunoprecipitation (ChIP) assay showed enrichment of MBD3 (methyl binding domain protein 3) to a higher degree than commonly associated MBDs and MeCP2. We evaluated the methylation pattern in 66 prostate cancer and 34 benign prostatic hyperplasia tissue samples. TMS1/ASC gene methylation was more prevalent in prostate cancer cases than controls in White patients (OR 7.6, p 0.002) while no difference between the cases and controls was seen in Black patients (OR 1.1, p 0.91).ConclusionOur study demonstrates that methylation-mediated silencing of TMS1/ASC is a frequent event in prostate cancer, thus identifying a new potential diagnostic and prognostic marker for the treatment of the disease. Racial differences in TMS1/ASC methylation patterns implicate the probable role of molecular markers in determining in susceptibility to prostate cancer in different ethnic groups.
Highlights
Transcriptional silencing associated with aberrant promoter methylation has been established as an alternate pathway for the development of cancer by inactivating tumor suppressor genes
We studied the prevalence of TMS1/ASC gene methylation in prostate cancer tissue samples as well as the association of race and clinico-pathological features with TMS1/ASC gene methylation
To determine if methylation was responsible for down regulation of TMS1/ASC in prostate cancer cell lines, we performed methylationspecific PCR (MS-PCR) using both methylated and unmethylated primers (Fig 2C)
Summary
Transcriptional silencing associated with aberrant promoter methylation has been established as an alternate pathway for the development of cancer by inactivating tumor suppressor genes. Gene silencing associated with aberrant promoter methylation has been suggested as an alternate pathway for development of cancer [1]. This form of epigenetic change contributes to tumor initiation and progression by transcriptional silencing of tumor-suppressor genes. Several genes have been shown to be epigenetically inactivated in a wide range of tumors [2] and most neoplasms show hypermethylation of one or more genes [3,4,5]. Several key genes involved in apoptosis have been showed to be target of epigenetic changes [9]
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