Research Papers:

Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3'-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma

Shinsuke Fujii _, Keiko Shinjo, Shinji Matsumoto, Takeshi Harada, Satoshi Nojima, Sunao Sato, Yu Usami, Satoru Toyosawa, Eiichi Morii, Yutaka Kondo and Akira Kikuchi

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Oncotarget. 2016; 7:81571-81587. https://doi.org/10.18632/oncotarget.13147

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Shinsuke Fujii1,5, Keiko Shinjo2, Shinji Matsumoto1, Takeshi Harada1, Satoshi Nojima3, Sunao Sato4, Yu Usami4, Satoru Toyosawa4, Eiichi Morii3, Yutaka Kondo2, Akira Kikuchi1

1Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan

2Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

3Department of Pathology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan

4Department of Oral Pathology, Graduate School of Dentistry, Osaka University, Suita 565-0871, Japan

5Present address: Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan

Correspondence to:

Akira Kikuchi, email: [email protected]

Keywords: ARL4C, DNA methylation, CpG islands, tissue differential methylation region, lung cancer

Received: May 30, 2016    Accepted: October 17, 2016    Published: November 07, 2016


ADP-ribosylation factor (ARF)-like 4c (ARL4C) expression, induced by a combination of Wnt/β-catenin and EGF/Ras signaling, has been demonstrated to form epithelial morphogenesis. ARL4C overexpression, due to Wnt/β-catenin and EGF/Ras signaling alterations, was involved in tumorigenesis. It was also reported that ARL4C expression correlates with DNA hypomethylation in the 3’-untranslated region (UTR) of ARL4C gene during lymphogenesis. The current study was conducted to investigate the expression and functions of ARL4C due to DNA hypomethylation in lung and tongue cancers. Immunohistochemical analyses of tissue specimens obtained from lung and tongue squamous cell carcinoma (SCC) patients revealed that ARL4C is not observed in non-tumor regions, but is strongly expressed at high frequencies in tumor lesions. Although inhibition of Wnt/β-catenin or Ras/MAP kinase signaling did not decrease ARL4C expression in NCI-H520 lung SCC cells, ARL4C DNA was clearly hypomethylated in the 3’-UTR. Ten-eleven translocation methylcytosine dioxygenase (TET) enzyme, which mediates DNA demethylation, was highly expressed in NCI-H520 cells. Knockout of TET family proteins (TET1-3) in NCI-H520 cells reduced 5-hydroxymethylcytosine (5hmC) levels and promoted DNA methylation in the 3’-UTR, leading to the decrease in ARL4C expression and ARL4C-mediated cellular migration. In tumor lesions of ARL4C-positive lung SCC, 5hmC was frequently detected and DNA methylation in the 3’-UTR of ARL4C gene was lower than in non-tumor regions, which were consistent with the Cancer Genome Atlas dataset. These results suggest that ARL4C is expressed due to hypomethylation in the 3’-UTR for certain types of cancers and that ARL4C methylation status is involved in cancer cell function.

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