Epigenetic inactivation of BCL6B, a novel functional tumour suppressor for gastric cancer, is associated with poor survival

Lixia Xu; Xiaoxing Li; Eagle S H Chu; Guijun Zhao; Minnie Y Y Go; Qian Tao; Hongchuan Jin; Zhirong Zeng; Joseph J Y Sung; Jun Yu
July 2012
Gut;Jul2012, Vol. 61 Issue 7, p977
Academic Journal
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. INSET: Significance of this study.


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