CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression

He Zhang,Xiuchen Xuan,Chuxuan Wang,Qinrui Tan,Hefei Wang,Yue Wu,Chaoxia Zou,Chendan Zou,Zini Qiu,Guixiang Lv,Wanli Yin,Dayong Wang,Yayan Wang,Cheng Zhan ,Erhu Fang ,Qiang Li,Yongjian Zhang,Cedric Matunda,Miao Chen,Xu Gao

doi:10.1038/s41419-020-02984-y

Abstract

Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein. We had reported that CPEB3 is involved in hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of CPEB3 in HCC remain unclear. In this study, we firstly performed RNA immunoprecipitation to uncover the transcriptome-wide CPEB3-bound mRNAs (CPEB3 binder) in HCC. Bioinformatic analysis indicates that CPEB3 binders are closely related to cancer progression, especially HCC metastasis. Further studies confirmed that metadherin (MTDH) is a direct target of CPEB3. CPEB3 can suppress the translation of MTDH mRNA in vivo and in vitro. Besides, luciferase assay demonstrated that CPEB3 interacted with 3′-untranslated region of MTDH mRNA and inhibited its translation. Subsequently, CPEB3 inhibited the epithelial–mesenchymal transition and metastasis of HCC cells through post-transcriptional regulation of MTDH. In addition, cpeb3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis and subsequent lung metastasis. Our results also indicated that CPEB3 was a good prognosis marker, which is downregulated in HCC tissue. In conclusion, our results demonstrated that CPEB3 played an important role in HCC progression and targeting CPEB3-mediated mRNA translation might be a favorable therapeutic approach.

Highlights

A growing body of evidence suggests that tumor cells can highjack post-transcriptional machinery to trigger reprogramming of gene expression when challenged by internal or external stimuli, which in turn enhances tumor cell proliferation and metastasis [1,2]
We found that the mRNAs enriched in the IP-FLAG samples had more CPEC, CPBNC, hexanucleotide AAUAAA (Hex), and Pumilio-binding element (PBE) elements in their 3′-UTR than those enriched in the immunoglobulin G (IgG) samples (Fig. 1c)
The results showed that CPEC, CPENC, Hex, and PBE elements all involved in the interaction between Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) and its binders

Summary

Introduction

A growing body of evidence suggests that tumor cells can highjack post-transcriptional machinery to trigger reprogramming of gene expression when challenged by internal or external stimuli, which in turn enhances tumor cell proliferation and metastasis [1,2]. The CPEB family of proteins (CPEB1–4) are all sequence-specific RNA-binding proteins. Binding to cytoplasmic polyadenylation elements (CPEs), CPEBs can further recruit several functional proteins to regulate the poly(A) tail length of target mRNAs, resulting in translational activation or repression of its targets[5,6]. The C terminus, which includes two RNA recognition motif and a zinc-finger domain, is highly conserved among CPEBs7. While the highly variable N terminus containing regulatory sites may contribute to the distinct functions of CPEB family members[4]. Despite the structural similarities among CPEBs, the expression of CPEBs in different malignancies is highly variable as well as the functions of CPEBs8,9. Evidence has shown that CPEB1 is likely to act Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion