UHRF1 predicts poor prognosis by triggering cell cycle in lung adenocarcinoma.

Zhenbo Tu,Qiuping Zhang,Anlin Feng,Xinzhou Deng,Shengqi Hou

doi:10.1111/jcmm.15438

Abstract

Accumulating evidence suggests that ubiquitin‐like with plant homeodomain and ring finger domains 1 (UHRF1) is overexpressed in non‐small cell lung cancer (NSCLC); however, the expression and function of UHRF1 in the subtype of NSCLC are still unclear. Here, we investigate the expression and prognosis traits of UHRF1 in large NSCLC cohorts and explore the molecular characters during UHRF1 up‐regulation. We find that UHRF1 is predominantly overexpressed in lung squamous cell carcinoma (SCC). Surprisingly, the up‐regulated UHRF1 is only associated with the overall survival of lung adenocarcinoma (ADC) and knockdown of UHRF1 dramatically attenuates ADC tumorigenesis. Mechanically, we identify a hub gene that includes a total of 55 UHRF1‐related genes, which are tightly associated with cell cycle pathway and yield to the poor clinical outcome in ADC patients. What's more, we observe knockdown of UHRF1 only affects ADC cells cycle and induces cell apoptosis. These results suggest that up‐regulated UHRF1 only contributes to lung ADC survival by triggering cell cycle pathway, and it may be a prognostic biomarker for lung ADC patients.

Highlights

Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) known as ICBP90 in human and Np95 in mice, works by explicit binding hemi-methylated CG sites through its SET- and RING-associated domain to play a vital role in performing and maintaining DNA methylation through recruiting DNMT1 to hemi-methylated DNA sites in S phase, which is dependent on ubiquitination of histone H3 at lysine 23.1-5 UHRF1 is involved in multiple diseases through the regulation of methylation,[6,7] especially in tumours where the dysregulation of UHRF1 is frequently observed.[8,9,10]
As shown in our analysis, the UHRF1 expression in squamous cell carcinoma (SCC) was significantly higher than that in ADC. These results indicate the UHRF1 expression is significantly up-regulated in non-small cell lung cancer (NSCLC), especially in SCC
The results revealed that the patients with high expression of UHRF1 were associated with poor prognosis, indicated by GSE41271 (P = .0171), GSE30219 (P < .0001), GSE31210 (P = .0003), GSE50081 (P = .0005), GSE11969 (P = .0418) and GSE13213 (P = .0082) (Figure 2A-F)

Summary

| INTRODUCTION

Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) known as ICBP90 in human and Np95 in mice, works by explicit binding hemi-methylated CG sites through its SET- and RING-associated domain to play a vital role in performing and maintaining DNA methylation through recruiting DNMT1 to hemi-methylated DNA sites in S phase, which is dependent on ubiquitination of histone H3 at lysine 23.1-5 UHRF1 is involved in multiple diseases through the regulation of methylation,[6,7] especially in tumours where the dysregulation of UHRF1 is frequently observed.[8,9,10] In lung cancer, UHRF1 was significantly up-regulated in NSCLC compared with normal lung tissues[8] and was expressed preferentially in non-ADC.[11]. Massive studies have shared their results of expression profiling on the commonly used platform, which provide. Zhenbo Tu and Xinzhou Deng contributed to this work. |2 opportunity for computational prediction of biomarkers, drugs and its potential mechanisms.[12,13,14] By investigating the previously published gene expression microarray data, we set out to identify the expression profile and prognosis value of UHRF1 in NSCLC and its subtype, respectively, and further to elucidate the mechanism of how UHRF1 affects the subtype of NSCLC patients' prognosis

| MATERIALS AND METHODS

Findings

| DISCUSSION