C-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA

Bingyan Li,Kaiyue Liu,Chenfeng Wang,Debao Fang,Guang Zhang,Zhongyu Wang,Yang Yang,Yide Mei,Fang Wang

doi:10.1038/s41419-021-04330-2

Bingyan Li, Kaiyue Liu + Show 7 more

Open Access

https://doi.org/10.1038/s41419-021-04330-2

Copy DOI

Abstract

The c-Myc oncoprotein plays a prominent role in cancer initiation, progression, and maintenance. Long noncoding RNAs (lncRNAs) are recently emerging as critical regulators of the c-Myc signaling pathway. Here, we report the lncRNA USP2-AS1 as a direct transcriptional target of c-Myc. Functionally, USP2-AS1 inhibits cellular senescence and acts as an oncogenic molecule by inducing E2F1 expression. Mechanistically, USP2-AS1 associates with the RNA-binding protein G3BP1 and facilitates the interaction of G3BP1 to E2F1 3′-untranslated region, thereby leading to the stabilization of E2F1 messenger RNA. Furthermore, USP2-AS1 is shown as a mediator of the oncogenic function of c-Myc via the regulation of E2F1. Together, these findings suggest that USP2-AS1 is a negative regulator of cellular senescence and also implicates USP2-AS1 as an important player in mediating c-Myc function.

Highlights

Cellular senescence is defined as an irreversible cell cycle arrest triggered by diverse forms of stresses such as telomere erosion/ uncapping, DNA damage, oxidative stress, and oncogenic activation [1,2,3,4]
By analyzing our recently published RNA-seq data generated in A549 cells with or without c-Myc induction and public ENCODE c-Myc chromatin immunoprecipitation (ChIP)-seq datasets [40, 42], six indicated Long noncoding RNAs (lncRNAs) with no or little functional characterization were revealed as potential transcriptional targets of c-Myc (Supplementary Fig. S1A)
Five c-Myc-upregulated lncRNAs were further validated by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis in A549 cells (Supplementary Fig. S1B)

Summary

Introduction

Cellular senescence is defined as an irreversible cell cycle arrest triggered by diverse forms of stresses such as telomere erosion/ uncapping, DNA damage, oxidative stress, and oncogenic activation [1,2,3,4]. In agreement with a large number of c-Myc target genes, overexpression of c-Myc deregulates a series of biological processes such as cell cycle progression, cell growth, cell metabolism, protein synthesis, and genomic maintenance [24,25,26]. Such deregulation provides growth advantages for tumors and contributes to the oncogenic function of c-Myc. Of interest, the suppression of c-Myc triggers cellular senescence in diverse tumor types, while overexpression of c-Myc inhibits oncogene-induced senescence in melanoma [27, 28]. They indicate that suppression of cellular senescence is critical for the tumor-promoting effect of c-Myc

Methods

Results

Conclusion