Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer

Abstract

In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In this study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target. This article is protected by copyright. All rights reserved.

High WDR34 mRNA expression as a potential prognostic biomarker in patients with breast cancer as determined by integrated bioinformatics analysis

“…Previous studies have reported that mutations of WDR34 mRNA are primarily associated with short-rib polydactyly syndrome type III and severe asphyxiating thoracic dysplasia (8,9). Loss-of-function mutations of FBXW7, another WDR protein, have been identified in colorectal cancer (18%), uterine endometrial carcinoma (15%) and uterine carcinosarcoma (40%), suggesting that the interactions between FBXW7 and its substrates are interrupted by disrupting the structural integrity of the WDR domain (47,48). Notably, compounds targeting the WDR domain of FBXW7 are expected to antagonize binding of cyclin E and phenocopy the oncogenic effect of mutations that are recurrent in cancer (47).…”

Integrative genomic analyses identify WDR12 as a novel oncogene involved in glioblastoma

“…WD repeats are minimally conserved regions of about 40 amino acids typically bracketed by tryptophan-aspartic acid (WD) and glycine-histidine (GH; Raab et al, 2010) that proved to promote the formation of heterotrimeric or polyprotein complexes. WDR12, a member of WDRs, regulates a wide variety of physiological functions, including muscle differentiation, cardiac growth, T-regulatory cell function, and neuronal disorders (Higa et al, 2006;Xu et al, 2014;Yuan et al, 2019). Recent studies have shown that WDR12 is an essential factor in tumorigenesis and plays a dual role in different cancers (Wu et al, 2018).…”

WD repeat domain 48 promotes hepatocellular carcinoma progression by stabilizing c‐Myc

“…As a protein–protein scaffold, the WD40 protein plays an important role in signal transduction, RNA synthesis and processing, cell cycle regulation, apoptosis and so on 6 . Studies have shown that the WD40 protein is abnormally expressed in many kinds of human malignant tumours, such as liver cancer, colorectal cancer, lung cancer, oesophageal cancer, breast cancer, cervical cancer and so on 7–10 . WDR48 has been reported to regulate the activities of ubiquitin‐specific proteases USP1, USP12 and USP46.…”

“… 6 Studies have shown that the WD40 protein is abnormally expressed in many kinds of human malignant tumours, such as liver cancer, colorectal cancer, lung cancer, oesophageal cancer, breast cancer, cervical cancer and so on. 7 , 8 , 9 , 10 WDR48 has been reported to regulate the activities of ubiquitin‐specific proteases USP1, USP12 and USP46. The WDR48–USP1 complex acts as a regulator during DNA damage, especially in translation synthesis and Fanconi anaemia pathway.…”