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 journalArticle

36 Citations (Scopus)

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/)

Original languageEnglish
Pages (from-to)298-309
Number of pages12
JournalJournal of Pathology
Volume230
Issue number3
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Fingerprint

Epigenomics
Squamous Cell Carcinoma
Neoplasms
Methylation
High-Throughput Screening Assays
Mastication
Feeding Behavior
Alcohol Drinking
Smoking
Gene Expression
Growth
Genes

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Lee, C. H., Wong, T. S., Chan, J. Y. W., Lu, S. C., Lin, P., Cheng, A. J., ... Chang, J. Y. (2013). Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. Journal of Pathology, 230(3), 298-309. https://doi.org/10.1002/path.4173

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

In: Journal of Pathology, Vol. 230, No. 3, 07.2013, p. 298-309.

Research output: Contribution to journalArticle

Lee, CH, Wong, TS, Chan, JYW, Lu, SC, Lin, P, Cheng, AJ, Chen, YJ, Chang, JSM, Hsiao, SH, Leu, YW, Li, CI, Hsiao, JR & Chang, JY 2013, 'Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma', Journal of Pathology, vol. 230, no. 3, pp. 298-309. https://doi.org/10.1002/path.4173
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. / Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. In: Journal of Pathology. 2013 ; Vol. 230, No. 3. pp. 298-309.
@article{e50f5bbfb5a347c9abe3bec77a8ea47b,
title = "Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma",
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/)",
keywords = "BEX1, hypermethylation, LDOC1, male predominance, NF- κ B, risk factor exposure, X-linked tumour suppressor gene",
author = "Lee, {Chia Huei} and Wong, {Thian Sze} and Chan, {Jimmy Yu Wai} and Lu, {Shao Chun} and Pinpin Lin and Cheng, {Ann Joy} and Chen, {Yin Ju} and Chang, {Jeffrey Shu Ming} and Hsiao, {Shu Huei} and Leu, {Yu Wei} and Li, {Chuan I.} and Hsiao, {Jenn Ren} and Chang, {Jang Yang}",
year = "2013",
month = "7",
doi = "10.1002/path.4173",
language = "English",
volume = "230",
pages = "298--309",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma

AU - Lee, Chia Huei

AU - Wong, Thian Sze

AU - Chan, Jimmy Yu Wai

AU - Lu, Shao Chun

AU - Lin, Pinpin

AU - Cheng, Ann Joy

AU - Chen, Yin Ju

AU - Chang, Jeffrey Shu Ming

AU - Hsiao, Shu Huei

AU - Leu, Yu Wei

AU - Li, Chuan I.

AU - Hsiao, Jenn Ren

AU - Chang, Jang Yang

PY - 2013/7

Y1 - 2013/7

N2 - 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/)

AB - 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/)

KW - BEX1

KW - hypermethylation

KW - LDOC1

KW - male predominance

KW - NF- κ B

KW - risk factor exposure

KW - X-linked tumour suppressor gene

UR - http://www.scopus.com/inward/record.url?scp=84878771970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878771970&partnerID=8YFLogxK

U2 - 10.1002/path.4173

DO - 10.1002/path.4173

M3 - Article

C2 - 23362108

AN - SCOPUS:84878771970

VL - 230

SP - 298

EP - 309

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 3

ER -