TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer
Seiya Yokoyama1,2,3, Michiyo Higashi1,2, Hideaki Tsutsumida1, Jouji Wakimoto4, Tomofumi Hamada5, Edwin Wiest3, Kei Matsuo1, Ikumi Kitazono1, Yuko Goto1, Xin Guo1, Taiji Hamada1, Sohsuke Yamada1, Tsubasa Hiraki1, Suguru Yonezawa1, Surinder K. Batra6, Michael A. Hollingsworth3, Akihide Tanimoto1
1 Department of Pathology, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Sakuragoaka, Japan
2 Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan
3 Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, NE, USA
4 Department of Respiratory Medicine, Minami-kyushu National Hospital, Aira, Japan
5 Department of Oral Surgery, Kagoshima University Medical and Dental Hospital, Sakuragoaka, Japan
6 Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, NE, USA
Correspondence:
Michiyo Higashi, email:
Keywords: Lung cancer, pathology, DNA methylation, risk factor, MUC4
Received: April 25, 2017 Accepted: June 14, 2017 Published: June 19, 2017
Abstract
Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.
