AUTHOR=He Jun-Ju , Li Zhi , Rong Zhuo-Xian , Gao Jie , Mu Yun , Guan Yi-Di , Ren Xin-Xin , Zi Yu-Yuan , Liu Li-Yu , Fan Qi , Zhou Ming , Duan Yu-Mei , Zhou Qin , Deng Yue-Zhen , Sun Lun-Quan 

TITLE=m6A Reader YTHDC2 Promotes Radiotherapy Resistance of Nasopharyngeal Carcinoma via Activating IGF1R/AKT/S6 Signaling Axis

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01166

DOI=10.3389/fonc.2020.01166

ISSN=2234-943X

ABSTRACT=<p>N6-methyladenosine (m<sup>6</sup>A) modification has been reported as a critical regulator of gene transcript expression. Although m<sup>6</sup>A modification plays important roles in tumor development, its role in therapeutic resistance remains unknown. In this study, we aimed to examine the expression level of m<sup>6</sup>A-modification related proteins and elucidate the effect of m<sup>6</sup>A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m<sup>6</sup>A modification, YTHDC2, a m<sup>6</sup>A reader, was found to be consistently highly expressed in radioresistant NPC cells. Knocking down of YTHDC2 expression in radioresistant NPC cells improved the therapeutic effect of radiotherapy <italic>in vitro</italic> and <italic>in vivo</italic>, whereas overexpression of YTHDC2 in radiosensitive NPC cells exerted an opposite effect. Bioinformatics and mechanistic studies revealed that YTHDC2 could physically bound to insulin-like growth factor 1 receptor (IGF1R) messenger RNA and promoted translation initiation of IGF1R mRNA, which in turn activated the IGF1R-AKT/S6 signaling pathway. Thus, the present study suggests that YTHDC2 promotes radiotherapy resistance of NPC cells by activating the IGF1R/ATK/S6 signaling axis and may serve as a potential therapeutic target in radiosensitization of NPC cells.</p>