Abstract
WD repeat protein 79 (WDR79) is a member of the WD‐repeat protein family characterized by the presence of a series of WD‐repeat domains and is a scaffold protein that participates in telomerase assembly, Cajal body formation and DNA double strand break repair. Although previous studies have revealed that WDR79 is frequently overexpressed in non‐small cell lung cancer (NSCLC) and promotes the proliferation of NSCLC cells, the underlying mechanism responsible for WDR79‐mediated NSCLC proliferation is not fully understood. In this study, we report a novel molecular function of WDR79 that mediates NSCLC cell proliferation by controlling the stability of UHRF1. In the nucleus, WDR79 colocalized and interacted with UHRF1. As a result, overexpression of WDR79 stabilized UHRF1, whereas ablation of WDR79 decreased the level of UHRF1. Meanwhile, we showed that WDR79 can protect UHRF1 from poly‐ubiquitination‐mediated proteolysis, which facilitated the stabilization of UHRF1. We further demonstrated that WDR79 exerts a proliferation effect on NSCLC cells by stabilizing UHRF1. These findings reveal that WDR79 is a novel UHRF1 regulator by maintaining UHRF1 stability, and they also provide a clue as to how to explore WDR79 for potential therapeutic application in NSCLC.
Highlights
Lung cancer is the disease with the highest morbidity and mortality rate in the world.[1]
Our previous studies revealed that with a tryptophan-aspartic acid (WD) repeat protein 79 (WDR79) is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer and promotes the proliferation of Non-Small Cell Lung Cancer (NSCLC) cells,[15,16] which is consistent with a recent study.[17]
We found that WDR79 was frequently overexpressed in cell lines and tissues derived from NSCLC, and it enhanced the proliferation of NSCLC cells both in vitro and in vivo.[15,16]
Summary
Lung cancer is the disease with the highest morbidity and mortality rate in the world.[1]. Non-Small Cell Lung Cancer (NSCLC) is the predominant type of lung cancer and accounts for approximately 80%-85% of all lung cancer cases. Our previous studies revealed that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer and promotes the proliferation of NSCLC cells,[15,16] which is consistent with a recent study.[17]. UHRF1 serves as a E3 ubiquitin-protein ligase to promote ubiquitylation of histone H3 by its RING domain, which provides the docking site for DNMT1.19 Studies have shown that the UHRF1 protein is regulated at both transcriptional and post-translational levels. Previous studies reveal that UHRF1 is overexpressed in almost all histological types of lung cancer and correlates with a poor prognosis, which can be useful for diagnosis of lung cancer in all pathological stages.[25]. WDR79 positively regulates UHRF1 stability by protecting it from ubiquitin-mediated degradation, and this positive regulation of UHRF1 by WDR79 mediates the proliferation of NSCLC
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