MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma

Mingyu Du,Yang Li,Lirong Wu,Huanfeng Zhu,Wenyue Sun,Jing Wu,Xia He,Yi Peng,Dan Zong

doi:10.1038/s41420-022-00844-6

Abstract

N6-Methyladenosine (m6A) modification is the most abundant RNA modification in eukaryotic cells. IGF2BP3, a well-known m6A reader, is deregulated in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains unclear. In this work, IGF2BP3 was upregulated in NPC tissues and cells. The high level of IGF2BP3 was positively related to late clinical stages, node metastasis, and poor outcomes. Moreover, IGF2BP3 accelerated NPC cell tumor progression and metastasis in vitro and vivo. Upstream mechanism analyses indicated that the high expression of IGF2BP3 in head and neck tumors was mainly due to mRNA level amplification. Luciferase assay and chromatin immunoprecipitation assay (CHIP) depicted that MYC was effectively bound to the promoter of IGF2BP3, thereby improving its transcriptional activity. Results also showed that IGF2BP3 was not only positively correlated with KPNA2 expression but also modulated the expression of KPNA2. m6A RNA immunoprecipitation (MeRIP) and RNA stability experiments verified that silencing IGF2BP3 significantly inhibited the m6A modification level of KPNA2, thereby stabilizing the mRNA stability of KPNA2. Rescue experiments proved that the effect of inhibiting or overexpressing IGF2BP3 on NPC cells was partly reversed by KPNA2. Collectively, MYC-activated IGF2BP3 promoted NPC cell proliferation and metastasis by influencing the stability of m6A-modified KPNA2. Our findings offer new insights that IGF2BP3 may serve as a new molecular marker and potential therapeutic target for NPC treatment.

Highlights

Nasopharyngeal carcinoma (NPC) is a prevalent and malignant head-and-neck tumor arising from the epithelial lining of nasopharynx
We identified for the first assays were conducted to verify the biological effects of IGF2BP3 time an oncogenic axis consisting of MYC-IGF2BP3-KPNA2
As an example of such mechanism, METTL3 mediates m6A modification of TRIM11 mRNA to stabilize its transcript via the m6A reader IGF2BP2-dependent pathway, thereby exacerbating drug resistance in NPC [21]

Summary

INTRODUCTION

Nasopharyngeal carcinoma (NPC) is a prevalent and malignant head-and-neck tumor arising from the epithelial lining of nasopharynx. M6A readers, such as YTH domain family proteins, IGF2BPs, HNRNPC, HNRNPA2/ B1, and eIF3, are needed to perform biological functions. These regulators lead to the dynamic and reversible modification process of m6A. Increasing lines of evidence have proved that the deviant expression of m6A modification may be the cause of tumor progression [13,14,15], the mechanism through which m6A regulators, especially IGF2BP3, function in NPC tumorigenesis remains unknown. The EDU assays showed that the number of molecular mechanism by which IGF2BP3 regulates target mRNA cells in the proliferation phase of siIGF2BP3-transfected cells was transcripts in an m6A-dependent manner. The inhibition effect in siIGF2BP3 group in the Transwell assay indicated that knockdown of IGF2BP3

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT