The Clinical Significance and Transcription Regulation of a DNA Damage Repair Gene, SMC4, in Low-Grade Glioma via Integrated Bioinformatic Analysis.

Yan Wang,Zhisheng Wu

doi:10.3389/fonc.2021.761693

Abstract

Glioma is the most common type of malignant tumor in the central nervous system with an unfavorable prognosis and limited treatment. In this study, we are devoted to addressing the prognostic value of DNA damage repair-related genes in low-grade glioma (LGG). We plotted the landscape of DNA damage repair (DDR)-related genes and identified SMC4 as an independent prognostic marker with integrated bioinformatics analysis, which is overexpressed in different histologic subtypes of glioma. We observed that SMC4 expression is elevated in recurrent LGG patients or those with advanced histologic staging. SMC4 depletion inhibits proliferation and induces increased replication damage in LGG cells. Lastly, we predicted and validated the transcription modulation of SMC4 by a transcription factor, MYB, at the -976bp~ -837bp of the SMC4 promoter region in LGG cells. Together, our study identified SMC4 as a potential prognostic biomarker for LGG patients, which functions to promote cell proliferation by repairing replication damage and the expression of SMC4 could be transcriptionally regulated by MYB.

Highlights

Glioma is the most prevalent primary malignant brain tumor in adults and is canonically categorized into 4 different stages, among which grade II and III frequently possess IDH mutation, collectively termed as low-grade glioma (LGG) [1]
We started by demonstrating the expression pattern of LGG patients in a DNA damage repair (DDR) perspective
While LGG is typically considered heterogenous, we noticed a cluster of DDR genes with homogenous expression patterns and defined these genes as the signature for DDR

Summary

INTRODUCTION

Glioma is the most prevalent primary malignant brain tumor in adults and is canonically categorized into 4 different stages, among which grade II and III frequently possess IDH mutation, collectively termed as low-grade glioma (LGG) [1]. Many cells from diverse histological origins are conserved in the DNA damage repair (DDR) pathways [7, 8]. The role of DDR, especially mismatch repair pathways in several cancer types has been discussed, the function of these genes in LGG has not been unveiled [12–14]. While the gene expression and cellular landscape of several brain tumors have been unveiled with single cell sequencing, the DNA damage repair landscape of glioma is still lacking due to the relatively low expression level. SMC4 is highly conserved across species and is observed to be overexpressed in multiple solid tumors, including hepatocellular carcinoma, colorectal cancer, and prostate cancer, etc. Recent studies have unveiled its correlation with tumor proliferation, differentiation, and vascular invasion in different cancers and suggested that miR-219 might be responsible for the regulation of SMC4 expression [18, 21]. The expression of SMC4 in brain tumors, such as LGG, and its canonical regulation by transcription factors or DNA methylation status are unknown

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DATA AVAILABILITY STATEMENT