Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma
Journal
Journal of Pathology
Journal Volume
230
Journal Issue
3
Pages
298-309
Date Issued
2013
Author(s)
Lee C.-H.
Wong T.-S.
Chan J.Y.-W.
SHAO-CHUN LU
Lin P.
Cheng A.-J.
Chen Y.-J.
Chang J.S.-M.
Hsiao S.-H.
Leu Y.-W.
Li C.-I.
Hsiao J.-R.
Chang J.-Y.
Abstract
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/) Copyright ? 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subjects
BEX1; hypermethylation; LDOC1; male predominance; NF- κ B; risk factor exposure; X-linked tumour suppressor gene
SDGs
Other Subjects
actin; alcohol dehydrogenase; aldehyde dehydrogenase; carbonate dehydratase III; carbonate dehydratase IV; cysteine dioxygenase; cytochrome c oxidase; endothelin 3; glutamate receptor; growth differentiation factor 10; hemoglobin A2; heparan sulfate; immunoglobulin enhancer binding protein; laminin alpha2; leucine zipper protein; metallothionein III; mitochondrial creatine kinase; nerve cell adhesion molecule; osteogenin; peroxisome proliferator activated receptor gamma; platelet derived growth factor D; potassium channel; proenkephalin; prostacyclin; prostaglandin E receptor 3; protein p50; protein tyrosine phosphatase; somatomedin C; stromal cell derived factor 1; synaptotagmin I; animal experiment; animal model; article; brain expressed X linked 1 gene; cancer inhibition; cell growth; cohort analysis; controlled study; DNA methylation; epigenetics; gene inactivation; genetic screening; high throughput screening; human; human cell; human tissue; in vitro study; in vivo study; leucine zipper down regulated in cancer 1 gene; molecular pathology; mouse; mouth squamous cell carcinoma; nonhuman; nucleotide sequence; priority journal; promoter region; sex difference; signal transduction; tumor suppressor gene; Animals; Carcinoma, Squamous Cell; Cell Line; Cohort Studies; DNA Methylation; Down-Regulation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, X-Linked; High-Throughput Screening Assays; Humans; Male; Mice; Mice, SCID; Mouth Neoplasms; Nerve Tissue Proteins; NF-kappa B; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Random Allocation; Sex Factors; Signal Transduction; Tumor Markers, Biological; Tumor Suppressor Proteins
Type
journal article