DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study
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Hon-Yi Lin1,6,8, Shih-Kai Hung1,6, Moon-Sing Lee1,6, Wen-Yen Chiou1,6, Tze-Ta Huang 2,6,7, Chih-En Tseng3,6, Liang-Yu Shih3,6, Ru-Inn Lin1,6,8, Jora M.J. Lin8,9, Yi-Hui Lai8,9, Chia-Bin Chang8,9, Feng-Chun Hsu1, Liang-Cheng Chen1, Shiang-Jiun Tsai1, Yu-Chieh Su4,6, Szu-Chi Li4,6, Hung-Chih Lai4,6, Wen-Lin Hsu5,6, Dai-Wei Liu5,6, Chien-Kuo Tai8,9, Shu-Fen Wu8,9 and Michael W.Y. Chan8,9,10
1 Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC
2 Department of Oral and Maxillofacial Surgery, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC
3 Department of Anatomic Pathology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC
4 Department of Hematology-Oncology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC
5 Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, ROC
6 School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC
7 Institute of Oral Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
8 Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC
9 Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC
10 Human Epigenomics Center, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC
Michael W.Y. Chan, email:
Keywords: Epigenetics, FHIT, oral cancer, radiotherapy, resistance
Received: September 03, 2014 Accepted: November 24, 2014 Published: November 25, 2014
Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using a methylation microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation, H3K27me3 and overexpression of methyltransferase EZH2 in OML1-R cells. Epigenetic interventions or depletion of EZH2 restored FHIT expression. Ectopic expression of FHIT inhibited tumor growth in both in vitro and in vivo models, while also resensitizing radioresistant cancer cells to irradiation, by restoring Chk2 phosphorylation and G2/M arrest. Clinically, promoter hypermethylation of FHIT inversely correlated with its expression and independently predicted both locoregional control and overall survival in 40 match-paired oral cancer patient samples. Further in vivo therapeutic experiments confirmed that inhibition of DNA methylation significantly resensitized radioresistant oral cancer cell xenograft tumors. These results show that epigenetic silencing of FHIT contributes partially to radioresistance and predicts clinical outcomes in irradiated oral cancer. The radiosensitizing effect of epigenetic interventions warrants further clinical investigation.
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