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

Hon Yi Lin, Shih Kai Hung, Moon Sing Lee, Wen Yen Chiou, Tze Ta Huang, Chih En Tseng, Liang Yu Shih, Ru Inn Lin, Jora M.J. Lin, Yi Hui Lai, Chia Bin Chang, Feng Chun Hsu, Liang Cheng Chen, Shiang Jiun Tsai, Yu Chieh Su, Szu Chi Li, Hung Chih Lai, Wen Lin Hsu, Dai Wei Liu, Chien Kuo TaiShu Fen Wu, Michael W.Y. Chan

研究成果: Article

13 引文 斯高帕斯(Scopus)

摘要

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 hypofractionated 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.

原文English
頁(從 - 到)915-934
頁數20
期刊Oncotarget
6
發行號2
DOIs
出版狀態Published - 2015 一月 1

    指紋

All Science Journal Classification (ASJC) codes

  • Oncology

引用此

Lin, H. Y., Hung, S. K., Lee, M. S., Chiou, W. Y., Huang, T. T., Tseng, C. E., Shih, L. Y., Lin, R. I., Lin, J. M. J., Lai, Y. H., Chang, C. B., Hsu, F. C., Chen, L. C., Tsai, S. J., Su, Y. C., Li, S. C., Lai, H. C., Hsu, W. L., Liu, D. W., ... Chan, M. W. Y. (2015). DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: An outcome-predicting and treatment-implicating study. Oncotarget, 6(2), 915-934. https://doi.org/10.18632/oncotarget.2821