DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study

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