RNA-binding protein p54nrb/NONO potentiates nuclear EGFR-mediated tumorigenesis of triple-negative breast cancer

Mengqin Shen,Ruixue Zhang,Zongping Zhu,Gang Huang,Li Zhao,Wenzhi Jia,Jianjun Liu

doi:10.1038/s41419-021-04488-9

Abstract

Nuclear-localized epidermal growth factor receptor (EGFR) highly correlates with the malignant progression and may be a promising therapeutic target for breast cancer. However, molecular mechanisms of nuclear EGFR in triple-negative breast cancer (TNBC) have not been fully elucidated. Here, we performed gene-annotation enrichment analysis for the interactors of nuclear EGFR and found that RNA-binding proteins (RBPs) were closely associated with nuclear EGFR. We further demonstrated p54nrb/NONO, one of the RBPs, significantly interacted with nuclear EGFR. NONO was upregulated in 80 paired TNBC tissues and indicated a poor prognosis. Furthermore, NONO knockout significantly inhibited TNBC proliferation in vitro and in vivo. Mechanistically, NONO increased the stability of nuclear EGFR and recruited CREB binding protein (CBP) and its accompanying E1A binding protein p300, thereby enhancing the transcriptional activity of EGFR. In turn, EGFR positively regulated the affinity of NONO to mRNAs of nuclear EGFR downstream genes. Furthermore, the results indicated that the nuclear EGFR/NONO complex played a critical role in tumorigenesis and chemotherapy resistance. Taken together, our findings indicate that NONO enhances nuclear EGFR-mediated tumorigenesis and may be a potential therapeutic target for TNBC patients with nuclear EGFR expression.

Highlights

15% of all diagnosed breast cancers are triplenegative breast cancer (TNBC)
NONO interacts with nuclear epidermal growth factor receptor (EGFR) To clarify the mechanism of nuclear EGFR, we investigated the nuclear interactome of EGFR obtained from BioGRID4.3 and STRING
Further analysis showed the expression of HSP90AB1, NONO, PRDX1, STIP1, YWHAZ were higher in TNBC tissue compared with non-TNBC tissue (Fig. S1A–C) and positively correlated with poor overall survival rates (Fig. S1D–F)

Summary

Introduction

15% of all diagnosed breast cancers are triplenegative breast cancer (TNBC). EGFR functions as a transcriptional mediator to activate the expression of cyclin D1 [8], B-Myb [9], COX-2 [10], Aurora A [11], c-Myc [12], BCRP [13], and iNOS [14], as a tyrosine kinase to phosphorylate and stabilize PCNA [15] and participated in DNA repair [16] These well-known targets are closely related to malignant phenotypes of TNBC, including tumorigenesis [17], cancer stemness [18, 19], metabolic reprogramming [20], and drug resistance [21], etc. The study of nuclear EGFR is still in its infancy

Methods

Results

Conclusion