FXR1 can bind with the CFIm25/CFIm68 complex and promote the progression of urothelial carcinoma of the bladder by stabilizing TRAF1 mRNA

Minhua Deng,Yulu Peng,Rixin Chen,Lijuan Jiang,Fangjian Zhou,Dan Xie,Zhuowei Liu,Zhiling Zhang,Ning Wang,Jinling Duan,Wensu Wei,Zeshen Wu,Zhiyong Li,Xianchong Zheng

doi:10.1038/s41419-022-04614-1

Abstract

RNA-binding proteins (RBPs) are key regulators of gene expression. RBP dysregulation is reported to play essential roles in tumorigenesis. However, the role of RBPs in urothelial carcinoma of the bladder (UCB) is only starting to be unveiled. Here, we comprehensively assessed the mRNA expression landscape of 104 RBPs from two independent UCB cohorts, Sun Yat-sen University Cancer Center (SYSUCC) and The Cancer Genome Atlas (TCGA). Fragile X-related gene 1 (FXR1) was identified as a novel cancer driver gene in UCB. FXR1 overexpression was found to be related to the poor survival rate in the SYSUCC and TCGA cohorts. Functionally, FXR1 promotes UCB proliferation and tumorigenesis. Mechanistically, FXR1 serves as a platform to recruit CFIm25 and CFIm68, forming a novel 3′ processing machinery that functions in sequence-specific poly(A) site recognition. FXR1 affects the 3′ processing of Tumor necrosis factor receptor-associated factor 1 (TRAF1) mRNA, which leads to nuclear stabilization. The novel regulatory relationship between FXR1 and TRAF1 can enhance cell proliferation and suppress apoptosis. Our data collectively highlight the novel regulatory role of FXR1 in TRAF1 3′ processing as an important determinant of UCB oncogenesis. Our study provides new insight into RBP function and provides a potential therapeutic target for UCB.

Highlights

Urothelial carcinomas are the most common cancers in urological systems, and more than 90% are urothelial carcinomas of the bladder (UCBs) [1]
We found that Fragile X-related gene 1 (FXR1) was frequently upregulated in urothelial carcinoma of the bladder (UCB) FXR1 interacts with the Tumor necrosis factor receptor-associated factor 1 (TRAF1) mRNA 3′ untranslated region tumors (Fig. 1F)
We investigated whether FXR1, cleavage factor Im 25 (CFIm25), and cleavage factor Im 68 (CFIm68) may function as a 3′ end processing complex on TRAF1 mRNA

Summary

INTRODUCTION

Urothelial carcinomas are the most common cancers in urological systems, and more than 90% are urothelial carcinomas of the bladder (UCBs) [1]. About 30% of newly diagnosed UCB patients have muscle-invasive bladder cancer (MIBC), which includes localized and metastatic disease [3]. Given the critical role of RBPs in many steps of gene expression, mutations or expression alterations of RBPs can frequently cause alterations in multiple biological and pathological processes that lead to diseases, including cancer [11,12,13,14]. Official journal of CDDpress complex for mRNA 3′ end processing that functions in sequence- baseline expression of FXR1 (Fig. 2A, Supplementary Fig 2A). Stable overexpression of FXR1 in 5637 cells, the tumorigenic functions of TRAF1 in UCB cells, enhancing cell which had low baseline expression of FXR1, markedly increased proliferation and suppressing apoptosis. Our study provides novel insight into RBP function generated a patient-derived organoid line of bladder cancer in and implies a potential therapeutic target for UCB. The results showed that FXR1 knockdown via short hairpin RNA (shRNA) lentiviral

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS APPROVAL