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Original article
Epigenetic inactivation of BCL6B, a novel functional tumour suppressor for gastric cancer, is associated with poor survival of gastric cancer
  1. Lixia Xu1,2,
  2. Xiaoxing Li1,
  3. Eagle S H Chu1,
  4. Guijun Zhao1,
  5. Minnie Y Y Go1,
  6. Qian Tao3,
  7. Hongchuan Jin3,
  8. Zhirong Zeng2,
  9. Joseph J Y Sung1,
  10. Jun Yu1
  1. 1Institute 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
  2. 2Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  3. 3Cancer Epigenetics Laboratory, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  1. Correspondence to Professor Jun Yu, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Rm 707A, Li Ka Shing Medical Sciences Building, PWH, Shatin, NT, Hong Kong SAR; junyu{at}cuhk.edu.hk

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.

  • B cell CLL/lymphoma 6 member B
  • gastric cancer
  • epigenetic alteration
  • methylation
  • tumour suppressor gene
  • prognosis
  • gastroscopy
  • tumour markers
  • methylation
  • gene regulation
  • molecular carcinogenesis
  • molecular oncology
  • carcinogenesis
  • cancer susceptibility
  • cancer immunobiology
  • cancer genetics
  • cancer prevention
  • colorectal adenomas
  • gastrointestinal bleeding
  • colorectal cancer screening
  • cancer
  • non-alcoholic steatohepatitis

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Footnotes

  • LX and XL contributed equally to the paper.

  • Funding This project was supported by National Natural Science Foundation of China (81172346), Research Grants Council RGC CERG CUHK (473008 and 465808), Group Research Scheme CUHK (3110043), CUHK Focused Investment Gant (2041423, 1903026), National Natural Science Foundation of China (81172346) and RFCID (10090942).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by the Clinical Research Ethics Committee of the Sun Yat-sen University of Medical Sciences and the Ethics Committee of the Chinese University of Hong Kong.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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