IL-37 Confers Anti-Tumor Activity by Regulation of m6A Methylation

Chunrui Yang,Xiaosong Gu,Jie Zhu,Qing Yan,Ketao Lan,Qi Zhao,Yuxiang Zhao,Ye Wang,Rui Peng,Wen Chen,Xiaofeng Mu

doi:10.3389/fonc.2020.526866

Abstract

N6-methyladenosine (m6A) is a common transcriptomic modification in cancer. Recently, it has been found to be involved in the regulation of non-small cell lung cancer (NSCLC) formation and metastasis. Interleukin 37 (IL-37) plays a crucial protective role in lung cancer. In our previous studies, we found that IL-37 is a potential novel tumor suppressor by inhibiting IL-6 expression to suppress STAT3 activation and decreasing epithelial-to-mesenchymal transition. Moreover, we found that treatment of IL-37 in lung cancer cells induced widespread and dynamic RNA m6A methylation. The effects of RNA m6A methylation of IL-37 treatment require further study. However, the functions of RNA m6A methylation of IL-37 treatment still await elucidation. Using MeRIP-seq and RNA-seq, we uncovered a unique m6A methylation profile in the treatment of IL-37 on the A549 cell line. We also showed the expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in A549 cells and lung cancer tissues after the treatment of IL-37. This study showed that IL-37 could lead to changes in m6A methylation level and related molecule expression level in A546 cells and may downregulate the proliferation by inhibiting Wnt5a/5b pathway in A549 cells. We conclude that IL-37 suppresses tumor growth through regulation of RNA m6A methylation in lung cancer cells.

Highlights

N6-methyladenosine (m6A) is a common RNA modification and has been shown to be critically important in the regulation of tumorigenesis of alternative splicing, stability, and translation [1]. m6A profiling experiments in various species revealed that its enrichment in ribosome-associated mRNA and near stop codons or long internal exons [2,3,4]
We found Interleukin 37 (IL-37) can inhibit cell invasion and metastasis through the IL-6/STAT3 signaling in nonsmall cell lung cancer (NSCLC) [24]
The protein expression of METTL14, WTAP, and AlkB homolog 5 (ALKBH5) decreased in IL-37 treated A549 cells, compared with that in non-treated control

Summary

Introduction

N6-methyladenosine (m6A) is a common RNA modification and has been shown to be critically important in the regulation of tumorigenesis of alternative splicing, stability, and translation [1]. m6A profiling experiments in various species revealed that its enrichment in ribosome-associated mRNA and near stop codons or long internal exons [2,3,4]. The role of m6A methylation is essential in various important biological processes, such as cellular differentiation, pluripotency, and stress response [10,11,12], in cancer stem cell self-renewal and differentiation. M6A may serve as an important pathway regulating initiation and progression in cancers [13, 14]. The IL-37 gene was mapped to chromosome 2, and the six exons of the IL-37 gene encode five isoforms (IL-37a–e). IL-37 acts as an anti-inflammatory cytokine by inhibiting innate responses [22] and plays a pivotal role in acute and chronic inflammation inflammation by balancing the cytokine expression [23]. IL-37 may serve as a potential key factor in restoring inflammatory balance in cancer development and treatment. How IL-37 affects cell growth and its underlying mechanisms have not been fully elucidated

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Conclusion