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

Abstract

N6-methyladenosine (m 6 A) modification has been reported as a critical regulator of gene transcript expression. Although m 6 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 6 A-modification related proteins and elucidate the effect of m 6 A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m 6 A modification, YTHDC2, a m 6 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 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.

m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer

“…In non-small cell lung cancer, down-regulation of the m6A reader YTHDC2 promotes tumor progression and predicts poor prognosis ( Sun et al, 2020 ). YTHDC2 activates the IGF1R/Akt/S6 signal axis to promote radiotherapy tolerance for nasopharyngeal carcinoma ( He et al, 2020 ). A previous study also showed a single nucleotide polymorphism (SNP) rs2416282 in the YTHDC2 gene promoter region is significantly associated with ESCC susceptibility ( Yang et al, 2020 ).…”

Significance of RNA N6-Methyladenosine Regulators in the Diagnosis and Subtype Classification of Childhood Asthma Using the Gene Expression Omnibus Database

“…Through its N-KIAA1429 domain, KIAA1429 acts as a bridge between the catalytic core component of METTL3/METTL14/WTAP and the RNA substrate, thus affecting the installation of m6A at specific sites ( He et al, 2019 ). YTHDC2 is a protein from the DExD/H box RNA helicase family that plays an important role in mRNA transcription and maintenance of mRNA stability ( He et al, 2020 ). ZC3H13 is a CCCH zinc finger protein ( Zhu et al, 2019 ).…”

“…It was reported that ZC3H13 may be a key upstream factor of nuclear factor-κB (NF-κB) that is responsible for NF-κB activation ( Luo et al, 2009 ). Numerous studies have shown that the five candidate m6A regulators participate in the occurrence and development of tumors, including proliferation, invasion, radiotherapy resistance, and prognosis ( Zalfa et al, 2017 ; Zhu et al, 2019 ; Chen et al, 2020 ; He et al, 2020 ; Xu et al, 2020 ). However, there are no reports on the relationship between the five candidate m6A regulators and childhood asthma.…”

Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases

“…In addition to promoting cisplatin resistance, FTO also contributed to radiation resistance in CSCC through up-regulation of [ 45 ]. YTHDC2 contributed to radioresistance in nasopharyngeal carcinoma (NPC) cells by binding to IGF1R mRNA and promoting the translation of the IGF1R transcript, leading to downstream activation of the IGF1R-AKT/S6 signaling axis [ 46 ].…”