Epigenetic regulation of the X‐linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. Issue 3 (21st March 2013)

• Record Type: Journal Article
• Authors: Lee, Chia‐Huei; Wong, Thian‐Sze; Chan, Jimmy Yu‐Wai; Lu, Shao‐Chun; Lin, Pinpin; Cheng, Ann‐Joy; Chen, Yin‐Ju; Chang, Jeffrey Shu‐Ming; Hsiao, Shu‐Huei; Leu, Yu‐Wei; Li, Chuan‐i; Hsiao, Jenn‐Ren; Chang, Jang‐Yang
• Is Part Of: Journal of pathology. Volume 230:Issue 3(2013)
• Page Start: 298
• Page End: 309
• Publication Date: 2013-03-21
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4173
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p> <bold>The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented; however, systemic analysis of OSCC is limited. Our study applied high‐throughput screening methods to identify causative epigenetic targets in a cohort of men with ABC‐associated OSCC. We identified <italic>BEX1</italic> and <italic>LDOC1</italic> as two epigenetically silenced X‐linked tumour suppressors and demonstrated a functional link between the transcription of <italic>BEX1</italic> and <italic>LDOC1</italic> and promoter hypermethylation. Methylation of the <italic>BEX1</italic> and <italic>LDOC1</italic> promoters was associated significantly (<italic>p <</italic> 0.0001) with OSCC and were detected in 75% (42/56) and 89% (50/56) of the samples, respectively. We observed concordant increases in the methylation of both genes in 71% (40/56) of the tumours, and potent <italic>in vitro</italic> and <italic>in vivo</italic> growth inhibitory effects in OSCC cells ectopically expressing BEX1 and/or <italic>LDOC1</italic>. Restored expression of <italic>BEX1</italic> and <italic>LDOC1</italic> suppressed the nuclear factor‐<italic>κ</italic>B (NF‐<italic>κ</italic>B) signalling pathway, which is the most frequently hyperactivated signalling pathway in OSCC. This suppression might result from decreased <italic>p50</italic> and <italic>p65</italic> expression. These findings suggest that silencing of <italic>BEX1</italic> and <italic>LDOC1</italic> by promoter hypermethylation might represent a critical event in the molecular pathogenesis of OSCC and account for the oncogenic effects of ABC exposure and the male predominance of OSCC occurrence. Microarray data are available in the Gene Expression Omnibus (GEO;</bold> http://www.ncbi.nlm.nih.gov/geo/<bold>) Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</bold></p> </abstract>