Abstract
Glioblastoma (GBM) is a type of brain cancer with high morbidity and mortality worldwide. The clinical significance, biological roles, and underlying molecular mechanisms of DNA poly ε-B subunit (POLE2) in GBM were investigated in the study. Firstly, the Cancer Genome Atlas (TCGA) database found that POLE2 was highly expressed in GBM. Immunohistochemistry (IHC) results further confirmed that POLE2 was abnormally elevated in GBM. In addition, loss-of-function assays revealed that POLE2 knockdown could inhibit the malignant behaviors of GBM, especially reduce cell viability, weaken cell clone formation, enhance the sensitivity of apoptosis, restrain migration and inhibit epithelial-mesenchymal transition (EMT) in vitro. In vivo experiments further clarified the suppressive effects of reduced POLE2 expression on tumors. Mechanically, POLE2 knockdown promoted the ubiquitination as well as reduced the stability of Forkhead transcription factor (FOXM1), which is a known tumor promotor in GBM, through Aurora kinase A (AURKA). Moreover, the knockdown of FOXM1 could weaken the promoting effects of POLE2 on malignant behaviors of GBM. In conclusion, our study revealed crucial roles and a novel mechanism of POLE2 involved in GBM through AURKA-mediated stability of FOXM1 and may provide the theoretical basis of molecular therapy for GBM.
Highlights
Glioma is one of the most common primary central nervous system tumors in adults, accounting for more than 70% of malignant brain tumors [1]
POLE2 is highly expressed in human GBM Firstly, we found that the mRNA expression of POLE2 in tumor samples (169 cases) was significantly higher compared with the normal samples (5 cases) from the Cancer Genome Atlas (TCGA) database (Fig. 1A)
The present study showed that knockdown of POLE2 resulted in the downregulation of phosphorylated Akt serine/threonine kinase (p-Akt), PIK3CA, G1 cyclin D1 (CCND1), and cyclin B1 (CCNB1) (Fig. 2E)
Summary
Glioma is one of the most common primary central nervous system tumors in adults, accounting for more than 70% of malignant brain tumors [1]. The World Health Organization (WHO) further divides astrocytomas into grade I (astrocytoma) and grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (pleomorphic glioblastoma) (GBM) [3]. The traditional treatment of glioma includes surgical resection, radiotherapy, and temozolomide (TMZ) adjuvant chemotherapy [4]. Grade I and II have slow growth, poor invasiveness, good prognosis, and sensitivity to treatment [5]. GBM are highly invasive and lethal, which are easy to relapse and have poor therapeutic effects due to resistance to chemotherapy and radiotherapy [6]. GBM has a poor prognosis, with an overall survival of less than 15 months after diagnosis [8]. The development of more effective and accurate therapies relies on the exploration of the molecular mechanisms of GBM.
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