ME2 Promotes Proneural-Mesenchymal Transition and Lipogenesis in Glioblastoma.

Mengting Yang,Aihua Gong,Xi Chen,Fei Fei,Li Li,Qianqian Wang,Ermeng Xiong,Wenjing Fang,Junyao Zhang

doi:10.3389/fonc.2021.715593

Abstract

Malic enzyme 2 (ME2) catalyzes the formation of pyruvate from malic acid and is abnormally expressed in some tumors. However, the exact effects of ME2 on proneural–mesenchymal transition (PMT) and lipogenesis in glioblastoma multiforme (GBM) remain unexplored. Here, we found that ME2 expression was significantly higher in GBM than in normal brain tissues and negatively correlated with overall survival of patients with GBM. Furthermore, we demonstrated that ME2 was positively correlated with mesenchymal features in GBM and promoted proliferation, migration, and invasion of glioma cells. Moreover, ME2 upregulated the expression of mesenchymal markers (N-cadherin, vimentin, YKL40, and MET), whereas it inhibited the expression of proneural maker OLIG2, indicating that ME2 might promote PMT in GBM. We also found that ME2 inhibited the production of mitochondrial reactive oxygen species and AMPK phosphorylation, resulting in SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. Taken together, these results suggest that ME2 promotes PMT and is linked with reprogramming of lipogenesis via AMPK–SREBP-1–ACSS2 signaling in GBM. Therefore, ME2 has potential as a new classification marker in GBM and could provide a new approach to glioma treatment.

Highlights

Glioblastoma multiforme (GBM) is the most common and fatal malignant primary brain tumor in adults, with a 5-year survival rate of less than 5% [1]
These results suggest that Malic enzyme 2 (ME2) is highly expressed in glioblastoma multiforme (GBM) and that its expression is negatively correlated with the total survival time of patients with GBM
We found that ME2 was correlated with the GBM MES phenotype and promoted proneural–mesenchymal transition (PMT) and reprograming of the lipogenesis pathway via AMPK–SREBP-1–ACSS2 in glioma cells

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and fatal malignant primary brain tumor in adults, with a 5-year survival rate of less than 5% [1]. The different GBM phenotypes, which include proneural (PN), neural, classical, and mesenchymal (MES) phenotypes, are relevant to the clinical treatment of recurrent brain tumors [5,6,7]. The MES phenotype is the most malignant and is associated with the worst prognosis, and the PN phenotype tends to transform into the MES phenotype [8, 9]. This PN–MES transition (PMT), a process similar to the epithelial–mesenchymal transition (EMT) that occurs in a variety of cancers, is a key event driving invasion, tumorigenesis, and development of gliomas [10,11,12]. In PMT, MES markers (including MET, vimentin, N-cadherin, and YKL-40) are positively correlated with tumor

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