Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma

Chia Huei Lee, Thian Sze Wong, Jimmy Yu Wai Chan, Shao Chun Lu, Pinpin Lin, Ann Joy Cheng, Yin Ju Chen, Jeffrey Shu Ming Chang, Shu Huei Hsiao, Yu Wei Leu, Chuan I. Li, Jenn Ren Hsiao, Jang Yang Chang

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)


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 BEX1 and LDOC1 as two epigenetically silenced X-linked tumour suppressors and demonstrated a functional link between the transcription of BEX1 and LDOC1 and promoter hypermethylation. Methylation of the BEX1 and LDOC1 promoters was associated significantly (p <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 in vitro and in vivo growth inhibitory effects in OSCC cells ectopically expressing BEX1 and/or LDOC1. Restored expression of BEX1 and LDOC1 suppressed the nuclear factor-κB (NF-κB) signalling pathway, which is the most frequently hyperactivated signalling pathway in OSCC. This suppression might result from decreased p50 and p65 expression. These findings suggest that silencing of BEX1 and LDOC1 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; http://www.ncbi.nlm.nih.gov/geo/)

Original languageEnglish
Pages (from-to)298-309
Number of pages12
JournalJournal of Pathology
Issue number3
Publication statusPublished - Jul 2013
Externally publishedYes


  • BEX1
  • hypermethylation
  • LDOC1
  • male predominance
  • NF- κ B
  • risk factor exposure
  • X-linked tumour suppressor gene

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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