WBSCR22 confers cell survival and predicts poor prognosis in glioma

Highlights

• WBSCR22 expression was upregulated in glioma tissues.

• Overexpression of WBSCR22 promotes glioma cell proliferation, migration and invasion.

• WBSCR22 may serve as the potential therapeutic target for glioma therapy.

Abstract

Human WBSCR22 is involved in cancer proliferation, invasion and metastasis; however, its function in glioma remains unexplored. In our research, we aimed to investigate the role of WBSCR22 in the development of glioma and its possible molecular mechanisms. Using bioinformatic analysis of public datasets, we determined that WBSCR22 overexpression in glioma specimens was correlated with an unfavorable patient prognosis. Our results revealed that WBSCR22 was highly expressed in glioma cell lines. The loss of WBSCR22 inhibited the growth, invasion and migration of glioma cells, while WBSCR22 overexpression produced the opposite effects. Moreover, we found that WBSCR22 downregulation reduced the phosphorylation of Akt and GSK3β and decreased the levels of β-catenin and CyclinD1 in glioma cells. The opposite effects were observed when WBSCR22 was overexpressed. Additionally, we verified with a dual-luciferase reporter assay that WBSCR22 was a direct target of miR-146b-5p. Furthermore, overexpression of miR-146b-5p suppressed WBSCR22 mRNA and protein expression. Notably, the restoration of WBSCR22 expression remarkably reversed the effects of miR-146b-5p overexpression on cell survival, apoptosis and the cell cycle in glioma cells. Collectively, our findings revealed a tumor-promoting role for WBSCR22 in glioma cells, thus providing molecular evidence for WBSCR22 as a novel therapeutic target in glioma.

Introduction

Gliomas are the most common and deadly primary carcinomas in the central nervous system. Gliomas are graded from I to IV according to the WHO criteria (Schreck et al., 2019). Malignant gliomas, especially grade IV astrocytomas known as glioblastoma (GBM), are aggressive and lethal tumors characterized by rapid growth, intratumoral heterogeneity, infiltrative growth behavior and recurrent neoplasms (Zhou and Wahl, 2019; Lapointe et al., 2018). Tremendous progress in glioma therapy involves developments in chemotherapy, surgical resection and radiation, but the median survival time of patients is less than 15 months from the time of diagnosis (Nalkiran and McDonald, 2017; Guo et al., 2018). Therefore, it is important to unveil the basis of potential molecular mechanisms of glioma biology and to identify biomarkers for diagnostic and therapeutic improvements in glioma treatment.

The WBSCR22 gene was first identified as one of 26 genes deleted in Williams-Beuren syndrome, which is characterized by unique cognitive delays, mental retardation, hypercalcemia, congenital heart and vascular disease, and dysmorphic facial features (Ounap et al., 2013). The WBSCR22 protein contains a nuclear localization signal and an S-adenosylmethionine (SAM) binding motif that is typical of a seven-β-strand, which may function in DNA methylation (Yan et al., 2015). WBSCR22 was reported to be overexpressed in both primary plasma cells and primary multiple myeloma tumor cells, and deletion of WBSCR22 was much more detrimental to myeloma cells than lung cancer cells, indicating its function in plasma cell biology (Tiedemann et al., 2012). Invasive breast cancer is characterized by WBSCR22 overexpression, and ectopic expression of WBSCR22 in nonmetastatic cells was found to enhance metastasis initiation by inhibiting Zac1/p53-dependent apoptosis (Nakazawa et al., 2011).

WBSCR22 is implicated in the pathogenesis of certain carcinomas in a context-dependent fashion; however, to date, the biological function of WBSCR22 in glioma remains to be determined. To better understand gliomas, we performed this research to explore the potential mechanisms of WBSCR22 in glioma pathogenesis.