Research Papers:

LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation

Chia-Huei Lee _, Kao-Lu Pan, Ya-Chu Tang, Ming-Hsien Tsai, Ann-Joy Cheng, Mei-Ya Shen, Ying-Min Cheng, Tze-Ta Huang and Pinpin Lin

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:25188-25201. https://doi.org/10.18632/oncotarget.4512

Metrics: PDF 1790 views  |   HTML 2044 views  |   ?  


Chia-Huei Lee1, Kao-Lu Pan2, Ya-Chu Tang1, Ming-Hsien Tsai2, Ann-Joy Cheng3, Mei-Ya Shen2, Ying-Min Cheng1, Tze-Ta Huang4, Pinpin Lin2

1National Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan

2National Institutes of Environmental Health Sciences, National Health Research Institutes, Taipei, Taiwan

3Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan City, Taiwan

4Department of Oral Medicine, National Cheng Kung University, Tainan City, Taiwan

Correspondence to:

Chia-Huei Lee, e-mail: [email protected]

Pinpin Lin, e-mail: [email protected]

Keywords: oral squamous cell carcinoma (OSCC), leucine-zipper downregulated in cancer 1 (LDOC1), cigarette smoke condensate (CSC), DNA methylation, malignant transformation

Received: January 22, 2015     Accepted: June 29, 2015     Published: July 10, 2015


Previously, we identified global epigenetic aberrations in smoking-associated oral squamous cell carcinoma (OSCC). We hypothesized that cigarette exposure triggers OSCC through alteration of the methylome of oral cells. Here we report that cigarette smoke condensate (CSC) significantly changes the genomic 5-methyldeoxycytidine content and nuclear accumulation of DNA methyltransferase 1 (DNMT1) and DNMT3A in human untransformed oral cells. By using integrated analysis of cDNA and methylation arrays of the smoking-associated dysplastic oral cell line and OSCC tumors, respectively, we identified four epigenetic targets—UCHL1, GPX3, LXN, and LDOC1—which may be silenced by cigarette. Results of quantitative methylation-specific PCR showed that among these four genes, LDOC1 promoter was the most sensitive to CSC. LDOC1 promoter hypermethylation and gene silencing followed 3 weeks of CSC treatment. LDOC1 knockdown led to a proliferative response and acquired clonogenicity of untransformed oral cells. Immunohistochemistry showed that LDOC1 was downregulated in 53.3% (8/15) and 57.1% (20/35) of premalignant oral tissues and early stage OSCCs, respectively, whereas 76.5% (13/17) of normal oral tissues showed high LDOC1 expression. Furthermore, the microarray data showed that LDOC1 expression had decreased in the lung tissues of current smokers compared with that in those of never smokers and had significantly decreased in the lung tumors of smokers compared with that in normal lung tissues. Our data suggest that CSC-induced promoter methylation may contribute to LDOC1 downregulation, thereby conferring oncogenic features to oral cells. These findings also imply a tumor suppressor role of LDOC1 in smoking-related malignancies such as OSCC and lung cancer.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4512