Inhibition of MUC1 exerts cell-cycle arrest and telomerase suppression in glioblastoma cells

Tamrin Chowdhury,Chae Eun Lee,Kyoungmi Kim,Soo-Ji Park,Youngbeom Seo,Ho Kang,Chul-Kee Park,Hak Jae Kim,Sojin Kim,Kyung-Min Kim,Hyeon Jong Yu

doi:10.1038/s41598-020-75457-z

Tamrin Chowdhury, Chae Eun Lee + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-75457-z

Copy DOI

Abstract

Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumorigenesis of diverse cancers. However, the role of MUC1 in glioblastoma (GBM) has not yet been fully explored. In this study, the anticancer mechanism of MUC1 suppression in GBM was investigated. The expression level of MUC1 was analyzed in human glioma and paired normal brain tissues. MUC1 was overexpressed in GBM and was negatively associated with overall survival. Moreover, we silenced MUC1 to investigate its effect in GBM cell lines and found that knockdown of MUC1 inhibited cell proliferation and resulted in cell cycle arrest at G1 phase. MUC1 silencing decreased the phosphorylation of RB1 and increased the expression of CDKN1B. Gene set enrichment analysis showed that a series of genes related to cell cycle, telomere maintenance and transforming growth factor Beta (TGF-β) signaling in epithelial mesenchymal transition (EMT) were influenced by MUC1 knockdown. Notably, the reduced TERT expression levels combined with impaired telomerase activity and the switching of telomere maintenance mechanism to alternative lengthening of telomeres (ALT) were observed after MUC1 knockdown. Our results support the role of MUC1 in oncological process in GBM which can be developed as a therapeutic target for cell cycle control and telomere maintenance mechanism.

Highlights

Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumorigenesis of diverse cancers
Using GBM and lower grade glioma (LGG) data from TCGA (The Cancer Genome Atlas) and normal brain data from GTEx (Genotype-Tissue Expression), we could confirm that the MUC1 was overexpressed in glioma tissue compared with normal brain (Fig. 1C)
We explored a functional role of MUC1 in tumorigenesis of GBM based on results from both in vitro experiments and genomic data of human samples

Summary

Introduction

Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumorigenesis of diverse cancers. Gene set enrichment analysis showed that a series of genes related to cell cycle, telomere maintenance and transforming growth factor Beta (TGF-β) signaling in epithelial mesenchymal transition (EMT) were influenced by MUC1 knockdown. Our results support the role of MUC1 in oncological process in GBM which can be developed as a therapeutic target for cell cycle control and telomere maintenance mechanism. Several prognostic genetic/epigenetic biomarkers, such as isocitrate dehydrogenase (IDH) mutation, human telomerase reverse transcriptase (hTERT) promoter mutation, and O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation have been identified through extensive molecular and genetic studies for glioblastoma[4] Among those biomarkers, hTERT promoter mutation is associated with expression of hTERT and elevation of telomerase activity (TA), which is one of the poor prognostic factor recently identified in gliomas[5]. The role of MUC1 has not been fully elucidated in GBM, only sporadic reports mentioned the MUC1 in relation to the maintenance of aggressive of g liomas[24]

Methods

Results

Conclusion