title: Epigenetic inactivation of BCL6B, a novel functional tumour suppressor for gastric cancer, is associated with poor survival.
abstract: OBJECTIVE
  Using genome-wide promoter methylation assay, B cell CLL/lymphoma 6 member B (BCL6B) was found to be preferentially methylated in cancer. A study was undertaken to examine the epigenetic regulation, biological function and clinical significance of BCL6B in gastric cancer (GC).
  
  
  METHODS
  BCL6B promoter methylation was evaluated by combined bisulfite restriction analysis and sequencing. The biological functions of BCL6B were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. The molecular targets of BCL6B were identified by cDNA expression array.
  
  
  RESULTS
  BCL6B was silenced or downregulated in all nine GC cell lines and readily expressed in normal gastric tissues. Loss of BCL6B expression was regulated by promoter hypermethylation. Re-expression of BCL6B in GC cell lines inhibited colony formation, suppressed cell viability, induced apoptosis and restrained the tumorigenecity in nude mice. These effects were associated with upregulation of the pro-apoptosis genes tumour necrosis factor receptor superfamily member 1A, caspase-8, caspase-9, caspase-3 and caspase-7 and nuclear enzyme poly (ADP-ribose) polymerase, downregulation of the pro-proliferation genes S100 calcium binding protein A4 and vascular endothelial growth factor A, and induction of the tumour suppressor genes ataxia telangiectasia mutated homologue and p53. BCL6B hypermethylation was detected in 49.0% (102/208) and 66.3% (67/101) of two independent cohorts of patients with GC, respectively. BCL6B methylation was an independent factor for the survival of patients with GC (p=0.001 for cohort I, p=0.02 for cohort II).
  
  
  CONCLUSIONS
  BCL6B plays a pivotal role as a potential tumour suppressor in GC. Detection of methylated BCL6B may serve as an independent biomarker for the prognosis of GC.
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
authors.forename: Lixia
authors.initials: L
authors.lastname: Xu
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Li
authors.forename: Eagle S H
authors.initials: ES
authors.lastname: Chu
authors.forename: Guijun
authors.initials: G
authors.lastname: Zhao
authors.forename: Minnie Y Y
authors.initials: MY
authors.lastname: Go
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zeng
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016019:Survival Analysis
chemical_list: C486398:BCL6B protein, human; D014408:Biomarkers, Tumor; D012097:Repressor Proteins