USP28 facilitates pancreatic cancer progression through activation of Wnt/\u03b2-catenin pathway via stabilising FOXM1

Leifeng Chen,Cihua Zheng,Yunyan Du,Qing Li,Zheng Xu,Xiaogang Peng,Qian Feng,Rongfa Yuan

doi:10.1038/s41419-021-04163-z

Abstract

Ubiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/β-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus β-catenin trans-activation, which in turn led to the activation of the Wnt/β-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/β-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.

Highlights

Pancreatic cancer (PC) is the seventh leading cause of cancerrelated deaths worldwide [1]
Ubiquitin-specific protease 28 (USP28) was overexpressed in human PC specimens and associated with poor prognosis To explore the role of USP28 in PC development, we examined USP28 expression in 102 PC tissue specimens and their
We found that USP28 promoted the proliferation, apoptosis, and tumorigenesis of PC cells, thereby indicating that USP28 may serve as an oncogene in PC

Summary

Introduction

Pancreatic cancer (PC) is the seventh leading cause of cancerrelated deaths worldwide [1]. Deubiquitinating enzymes (DUBs) counteract the activities of E3 ligases, and are implicated as important molecules that modulate ubiquitination [5, 6]. As a result, they have emerged as promising therapeutic targets for cancer treatment [7]. Recent studies have shown that USP28 is highly upregulated and is correlated with poor clinical prognosis in a variety of cancers, such as colon cancer [11], non-small cell lung cancer [12], and bladder cancer [13]. Because of its deubiquitinase activity, USP28 interacts with Myc to catalyse the deubiquitination of Myc, thereby promoting its stabilisation and contributing to tumour cell growth in colon and breast carcinomas [14]. The biological functions and expression patterns of USP28 in PC are not known

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