Journal Article

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

Liang, Zhen-xing, Yang, Xin, Lan, Ping, Xiong, Li, Wang, Feng-wei, Zeng, Zi-wei, Wu, Xian-rui, Liu, Hua-shan, He, Xiao-wen

2021

Overview

Background Constitutive 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. Methods We 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. Results A 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. Conclusions circPLCE1 presents an epigenetic mechanism which disrupts NF-κB nuclear translocation and serves as a novel and promising therapeutic target and prognostic marker.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line, Tumor / Cell Movement / Cell Proliferation / Chromatography, Liquid / circPLCE1 / Circular RNA / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Disease Models, Animal / Epigenetics / Epithelial cells / Gene Expression Regulation, Neoplastic / Humans / Immunoprecipitation / Metastases / Metastasis / Mice / Models, Biological / NF-kappa B - metabolism / NF-κB / NF-κB protein / Nuclear transport / Oncology / Phosphoinositide Phospholipase C - genetics / Proteins / Proteolysis / Proteomics - methods / Ribosomal Proteins - metabolism / RNA, Circular / Signal Transduction / Software / Statistical analysis / Tandem Mass Spectrometry / Therapeutic targets / Tumors / Ubiquitin / Ubiquitin - metabolism / Ubiquitination / Xenografts