An E3 Ubiquitin Ligase RNF139 Serves as a Tumor-Suppressor in Glioma

Xiaofeng Chen,Weiping Kuang,Xi Zhang,Shucheng Zou,Liang Li,Bin Zhou,Yong Zhu,Bo Li,Xiaosong Li

doi:10.1007/s12031-021-01860-4

Abstract

Glioma is highly lethal because of its high malignancy. Ubiquitination, a type of ubiquitin-dependent protein modification, has been reported to play an oncogenic or tumor-suppressive role in glioma development, depending on the targets. Ring finger protein 139 (RNF139) is a membrane-bound E3 ubiquitin ligase serving as a tumor suppressor by ubiquitylation-dependently suppressing cell growth. Herein, we firstly confirmed the abnormal downregulation of RNF139 in glioma tissues and cell lines. In glioma cells, ectopic RNF139 overexpression could inhibit, whereas RNF139 knockdown could aggravate the aggressive behaviors of glioma cells, including hyperproliferation, migration, and invasion. Moreover, in two glioma cell lines, RNF139 overexpression inhibited, whereas RNF139 knockdown enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT serine/threonine kinase 1 (AKT). In a word, we demonstrate the aberration in RNF139 expression in glioma tissue samples and cell lines. RNF139 serves as a tumor-suppressor in glioma by inhibiting glioma cell proliferation, migration, and invasion and promoting glioma cell apoptosis through regulating PI3K/AKT signaling.

Highlights

Glioma, the most common primary intracranial tumor accounting for more than 80% of craniocerebral malignant tumors, is highly lethal because of its high malignancy (Ostrom et al 2014)
Considering that the occurrence of glioblastoma multiform, the most malignant glioma, is highly relevant with changes in the factors of the epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin kinase signaling pathways (Chakravarti et al 2004; Li et al 2016), we investigated the alterations in the PI3K/AKT signaling in response to Ring finger protein 139 (RNF139) overexpression or knockdown
By contrast, when RNF139 was knocked down in glioma cell lines, cell viability (Fig. 2C, D), DNA synthesis (Fig. 2E, F), and cell migration and invasion (Fig. 3C–F) were all enhanced, whereas cell apoptosis was inhibited (Fig. 3A, B). These data indicate that ectopic RNF139 overexpression could inhibit, whereas RNF139 knockdown could aggravate the aggressive behaviors of glioma cells

Summary

Introduction

The most common primary intracranial tumor accounting for more than 80% of craniocerebral malignant tumors, is highly lethal because of its high malignancy (Ostrom et al 2014). RNF139 ( known as TRC8) is a membrane-bound E3 ubiquitin ligase, which plays a tumor-suppressive role (Gemmill et al 1998) by ubiquitylation-dependently suppressing cell growth (Brauweiler et al 2007). Regarding the tumor-suppressive functions, Brauweiler et al (Brauweiler et al 2007) reported RNF139-caused inhibition of human kidney cell proliferation by inducing cell cycle arrest in G2/M phase, inhibiting DNA synthesis, and promoting apoptosis. Considering that the occurrence of glioblastoma multiform, the most malignant glioma, is highly relevant with changes in the factors of the epidermal growth factor receptor (EGFR) and PI3K/Akt/mechanistic target of rapamycin kinase (mTOR) signaling pathways (Chakravarti et al 2004; Li et al 2016), we investigated the alterations in the PI3K/AKT signaling in response to RNF139 overexpression or knockdown. We observed that the tumor-suppressive role of RNF139 in glioma cells through regulating the possible downstream signaling (PI3K/AKT signaling). Our basic experimental outcomes provided sufficient results to uncover a newfound mRNA/signaling pathway regulatory network of RNF139/ PI3K/AKT signaling in glioma, supplying a crucial perception concerning the regulatory theory in glioma advancement and new therapeutic options of glioma diseases

Materials and Methods

Findings

Discussion