Methylation mediated silencing of TMS1/ASC gene in prostate cancer

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.

Epigenetic Regulation of HYAL-1 Hyaluronidase Expression

“…1A). No sumoylation sequence is found in the HYAL-1 protein (33). Consistent with this observation, HYAL-1 immunoprecipitation, followed by anti-sumo1 or anti-sumo2/3 immunoblotting, showed that HYAL-1 protein is not sumoylated (data not shown).…”

Racial disparities in prostate cancer a molecular perspective

“…observed that the CD44 and GSTP1 were not significantly different in terms of their methylation status between populations. However, significantly enhanced methylation of PYCARD (TMS1/ASC) in benign prostatic hyperplasia (BPH) was reported in AA cases (33). Despite these contradictory findings, the importance of epigenetic modifications cannot be undermined.…”

ASC contributes to metastasis of oral cavity squamous cell carcinoma

“…Indeed, accumulating information suggests that ASC may play multiple roles in cancer. For example: it can function as a tumor suppressor; its expression is decreased by promote methylation in cancers such as melanoma [23], breast cancer [24], ovarian cancer [25], prostate cancer [26], colorectal cancer [27] and hepatocellular carcinoma [28]; it is reportedly involved in the progression of melanoma [29]; and our group showed that it is highly elevated in NPC tumor cells, where its expression correlates with local recurrence and the survival of patients [22]. These findings prompted us to explore the potential role of inflammasome proteins in OSCC, which is believed to be associated with local inflammation.…”