Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer

R J Shaw, M M Omar, S Rokadiya, F A Kogera, D Lowe, G L Hall, J A Woolgar, J Homer, T Liloglou, J K Field, J M Risk

Research output: Contribution to journalArticle (journal)peer-review

57 Citations (Scopus)

Abstract

BACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract.

METHODS: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment.

RESULTS: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation.

CONCLUSION: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

Original languageEnglish
Pages (from-to)139-44
Number of pages6
JournalBritish Journal of Cancer
Volume101
Issue number1
DOIs
Publication statusPublished - 7 Jul 2009

Keywords

  • Carcinoma, Squamous Cell/genetics
  • Cell Hypoxia/genetics
  • Cell Line, Tumor
  • Cytoglobin
  • DNA Methylation
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Globins/biosynthesis
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
  • Mouth Neoplasms/genetics
  • Oropharyngeal Neoplasms/genetics
  • Promoter Regions, Genetic
  • RNA, Messenger/biosynthesis
  • Up-Regulation

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