UBQLN4 is activated by C/EBP\u03b2 and exerts oncogenic effects on colorectal cancer via the Wnt/\u03b2-catenin signaling pathway

Xiaolong Tang,Qingsi He,Yahang Liang,Guorui Sun,Hui Qu,Peng Gao

doi:10.1038/s41420-021-00795-4

Abstract

Ubiquilin 4 (UBQLN4) is an important member of the ubiquitin-like protein family. An increasing number of studies have shown that UBQLN4 is an important regulator of tumorigenesis. Nevertheless, the biological function and detailed mechanisms of UBQLN4 in colorectal cancer (CRC) development and progression remain unclear. Here, we identified UBQLN4 upregulation in CRC tissues and it is positively associated with CRC size, TNM stage, and lymphatic metastasis. Patients with high UBQLN4 expression had a poor prognosis. Functionally, overexpression of UBQLN4 significantly promoted CRC cell proliferation, migration, and invasion, while UBQLN4 silencing elicited the opposite effect. This result was consistent with the conclusion that UBQLN4 expression correlated positively with the CRC size and lymphatic metastasis. In vivo, UBQLN4 silencing also inhibited tumor growth. Mechanistically, using gene set enrichment analysis (GSEA) and western blot experiments, we identified that UBQLN4 activated the Wnt/β-catenin signaling pathway to upregulate β-catenin and c-Myc expression, thereby promoting CRC proliferation, migration and invasion. A rescue experiment further verified this conclusion. Dual luciferase reporter, real-time quantitative PCR (RT-qPCR), western blot and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) directly bound to the UBQLN4 core promoter region and activated its transcription, upregulating β-catenin and c-Myc expression to promote CRC progression. Thus, our findings suggest that UBQLN4 is a key oncogene in CRC and may be a promising target for the diagnosis and treatment of patients with CRC.

Highlights

Colorectal cancer (CRC) is the third most common malignant tumor and ranks second in cancer mortality worldwide, just after lung cancer [1, 2]
Ubiquilin 4 (UBQLN4) is upregulated in CRC and related to the CRC size, TNM stage, and lymphatic metastasis We detected the expression of UBQLN4 in CRC using The Cancer Genome Atlas (TCGA) database
UBQLN4 expression in CRC was higher than that in adjacent normal tissues (ANTs) (p < 0.001, Fig. 1A). We validated this result by measuring UBQLN4 expression in 50 paired CRC tissues and ANTs using real-time quantitative PCR (RT-qPCR) (Fig. 1B)

Summary

Introduction

Colorectal cancer (CRC) is the third most common malignant tumor and ranks second in cancer mortality worldwide, just after lung cancer [1, 2]. Most patients with advanced CRC still have a poor prognosis because of the high risk of recurrence and metastasis after surgery. Studies of the mechanisms leading to the recurrence and metastasis of CRC and active explorations of effective molecular therapeutic targets are crucial. The development and progression of CRC involves a wide variety of causes, including genetic mutations [6], abnormal gene fusions [7], copy number variations [8], epigenetic changes [9], and other processes. With the increase in the aforementioned mutations in the cells, the intracellular environment is disturbed, leading to cell carcinogenesis. Cells have numerous defense mechanisms against alterations in the intracellular environment, among which the ubiquitin–proteasome system is important. Abnormal ubiquitin–proteasome degradation pathways induce various diseases, including viral infectious diseases, congenital dysplasia, neurodegenerative diseases, and cancers [11,12,13,14]

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