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Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial

Katherine Karakoula1, Thomas S Jacques2, Kim P Phipps3

  • 1Brain Tumour Research Centre, School of Applied Sciences, University of Wolverhampton, Wolverhampton WV1 1LY, UK.

Cancer Letters
|December 17, 2013
PubMed

Insights

Epigenetic silencing of genes through promoter hypermethylation is common in paediatric intracranial ependymoma. Brain-expressed X-linked 1 (BEX1) was found to be epigenetically inactivated, acting as a tumor suppressor.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Promoter hypermethylation and transcriptional silencing are key epigenetic mechanisms for gene inactivation in cancer.
  • Understanding these mechanisms in paediatric intracranial ependymoma is crucial for identifying therapeutic targets.

Purpose of the Study:

  • To identify epigenetically silenced genes in paediatric intracranial ependymoma.
  • To investigate the role of these silenced genes in tumourigenesis.
  • To evaluate the therapeutic potential of targeting these genes.

Main Methods:

  • Pharmacological unmasking using 5-Aza-2'-deoxycytidine on ependymoma cell cultures.
  • Global expression microarray analysis to identify candidate silenced genes.
  • Combined bisulfite restriction analysis (COBRA), genomic sequencing, and real-time quantitative PCR to validate methylation and expression levels.
  • Ectopic expression of BEX1 to assess its functional role.

Main Results:

  • Identified 55 candidate epigenetically silenced genes involved in apoptosis, Wnt signalling, p53, and cell differentiation.
  • BEX1, BAI2, CCND2, and CDKN2A were the most frequently methylated genes.
  • Demonstrated a strong correlation between promoter hypermethylation and decreased gene expression.
  • Ectopic expression of BEX1 significantly inhibited ependymoma cell proliferation and colony formation.

Conclusions:

  • Promoter hypermethylation contributes to target gene silencing in paediatric intracranial ependymoma.
  • Epigenetic inactivation of BEX1 suggests its role as a tumour suppressor gene.
  • BEX1 represents a potential therapeutic target for childhood ependymoma.
Keywords:
5-Aza-dCBEX1DNA methylationPaediatric ependymomaPharmacological unmasking

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