A novel NF-\u03baB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation

Zhen-Xing Liang,Xiao-Wen He,Hua-Shan Liu,Zi-Wei Zeng,Li Xiong,Xian-Rui Wu,Feng-Wei Wang,Ping Lan,Xin Yang

doi:10.1186/s12943-021-01404-9

Abstract

BackgroundConstitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC). However, the underlying mechanisms of excessive activation of NF-κB signaling remain largely unknown.MethodsWe used high throughput RNA sequencing to identify differentially expressed circular RNAs (circRNAs) between normal human intestinal epithelial cell lines and CRC cell lines. The identification of protein encoded by circPLCE1 was performed using LC–MS. The function of novel protein was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses.ResultsA novel protein circPLCE1-411 encoded by circular RNA circPLCE1 was identified as a crucial player in the NF-κB activation of CRC. Mechanistically, circPLCE1-411 promoted the ubiquitin-dependent degradation of the critical NF-κB regulator RPS3 via directly binding the HSP90α/RPS3 complex to facilitate the dissociation of RPS3 from the complex, thereby reducing NF-κB nuclear translocation in CRC cells. Functionally, circPLCE1 inhibited tumor proliferation and metastasis in CRC cells, as well as patient-derived xenograft and orthotopic xenograft tumor models. Clinically, circPLCE1 was downregulated in CRC tissues and correlated with advanced clinical stages and poor survival.ConclusionscircPLCE1 presents an epigenetic mechanism which disrupts NF-κB nuclear translocation and serves as a novel and promising therapeutic target and prognostic marker.

Highlights

Constitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC)
We found that the circRNA circPLCE1 was downregulated in CRC tissues and was associated with clinical stages and survival
The expression levels of the 6 circRNAs were detected in 24 paired tissues by quantitative real-time PCR, which showed that only circPLCE1 was differently expressed between CRC samples and normal adjacent tissues (Figure S1B)

Summary

Introduction

Constitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC). The underlying mechanisms of excessive activation of NF-κB signaling remain largely unknown. Numerous studies have revealed that constitutive activation of NF-κB signaling pathway plays important roles in the development and progression of human cancers [4,5,6]. Liang et al Mol Cancer (2021) 20:103 constitutive activation of the NF-κB signaling pathway remain incompletely understood. Constitutive activation of NF-κB was shown to be correlated with advanced tumor stages and poor survival of CRC patients [7, 13]. The underlying mechanisms of excessive activation of NF-κB signaling pathway remain largely unknown in CRC

Methods

Results

Discussion

Conclusion