title: Methylation mediated silencing of TMS1/ASC gene in prostate cancer.
abstract: BACKGROUND
  Transcriptional 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.
  
  
  RESULTS
  Loss 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).
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA. pdmanas30@yahoo.com
authors.forename: Partha M
authors.initials: PM
authors.lastname: Das
authors.forename: Kavitha
authors.initials: K
authors.lastname: Ramachandran
authors.forename: Jane
authors.initials: J
authors.lastname: Vanwert
authors.forename: Larry
authors.initials: L
authors.lastname: Ferdinand
authors.forename: Gopal
authors.initials: G
authors.lastname: Gopisetty
authors.forename: Isildinha M
authors.initials: IM
authors.lastname: Reis
authors.forename: Rakesh
authors.initials: R
authors.lastname: Singal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D053468:CARD Signaling Adaptor Proteins; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C402202:PYCARD protein, human; C012589:trichostatin A; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine