LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation

Chia Huei Lee, Kao Lu Pan, Ya Chu Tang, Ming Hsien Tsai, Ann Joy3 Cheng, Mei Ya Shen, Ying Min Cheng, Tze Ta Huang, Pinpin Lin

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


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 methylationspecific 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.

Original languageEnglish
Pages (from-to)25188-25201
Number of pages14
Issue number28
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology


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