Abstract
N6-methyladenosine (m6A) modification has been reported as a critical regulator of gene transcript expression. Although m6A 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 m6A-modification related proteins and elucidate the effect of m6A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m6A modification, YTHDC2, a m6A 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 in vitro and in vivo, 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.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the epithelium of the nasopharynx, and most cases of nasopharyngeal carcinoma (NPC) usually occurred in Southeast Asia and Southern China [1,2,3]
To examine the expression of the genes involved in m6A modification, an analysis of an NPC transcriptome-sequencing dataset (GSE48501 including radiosensitive cell line CNE2 and radioresistant cell line CNE2-IRR) from the Gene expression Omnibus (GEO) database was performed
We found that YTH domain containing 2 (YTHDC2) expression was elevated in patient specimens of partial response (PR) compared to those of complete response (CR) (Figure 1D)
Summary
Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the epithelium of the nasopharynx, and most cases of NPC usually occurred in Southeast Asia and Southern China [1,2,3]. Radiotherapy (RT) is the preferred treatment for patients with NPC [4,5,6]. The molecular mechanism underlying radiation resistance should be thoroughly studied, with the aim to identify promising targets to alleviate radiotherapy resistance of patients with NPC. N6-methyladenosine (m6A) refers to methylation of the adenosine base at the nitrogen-6 position. It is the most abundant modification in messenger RNA [7] and is found in ribosomal RNA, transfer RNA, and small nuclear RNA as well as some non-coding RNA [8, 9].
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