miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities

Abstract

The development of glioblastoma (GBM) is typically accompanied by marked changes in lipid metabolism. Oxylipins and their catalyzed enzymes lipoxygenases (LOXs) have been shown to participate in the development of cancers via multiple pathways, while the understanding of LOXs in GBM remains enigmatic. Thus, we aimed to explore the expression and functional roles of LOXs in the development of GBM. Here we showed that ALOXE3 was markedly down-regulated in human GBM. Knockdown of ALOXE3 in GBM cells fostered the orthotopic tumor growth and shortened lifespan in mice. ALOXE3 deficiency rendered GBM cells resistant to p53-SLC7A11 dependent ferroptosis, promoting GBM cell survival. Mechanistically, miR-18a directly targeted ALOXE3 and suppressed its expression and functions in GBM cells. Furthermore, ALOXE3 silencing promoted 12-hydroxyeicosatetraenoic acids (12-HETE) secretion from GBM cells, in turn, 12-HETE enhanced migration of GBM cells by activating Gs-protein-coupled receptor (GsPCR)-PI3K-Akt pathway in an autocrine manner. Altogether, miR-18a/ALOXE3 axis exerts tumor promoting functions by regulating ferroptosis and migration of GBM cells. Targeting miR-18a/ALOXE3 axis may provide novel therapeutic approaches for GBM treatment.

Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation

“…YAP S127A mutant-overexpressing LM3 cells showed a significant enrichment of genes in categories related to peroxisome proliferator activated receptor signaling pathway, while parental cells were strongly characterized by the expression of genes involved in cysteine and methionine metabolism and glutathione metabolism. Among genes comprising the leading edge of Enrichment score in the category of peroxisome proliferator activated receptor signaling pathway in YAP S127A -overexpressing cells compared with parental cells, ALOXE3 belongs to the mammalian lipoxygenase family ( Figure 6C ), which has been revealed as a ferroptosis regulator ( Yang, Kim et al, 2016 ; Xia, Liu et al, 2020 ; Yang, Liu et al, 2021 ). Based on publicly available ENCODE TEAD4 ChIP-seq datasets (GSM1614035, GSM1010860, GSM1010868, GSM1010772 and GSM1010875), we found that ALOXE3 is a putative YAP-TEAD4 gene target in various cancer cell lines.…”

“…As a transcriptional coactivator, YAP regulates the expression of multiple target genes through its interaction with the TEAD family of transcriptional factors ( Zhao, Lei et al, 2008 ). YAP promote ferroptosis through upregulation of multiple ferroptosis modulators, including ACSL4, TFRC and SKP2 ( Wu, Minikes et al, 2019 ; Yang, Lin et al, 2021 ). This study reveals the lipoxygenase ALOXE3 as another YAP-TEAD target gene that contributed to YAP-promoted ferroptosis.…”

Development and Validation of a Ferroptosis-Related Gene Signature and Nomogram for Predicting the Prognosis of Esophageal Squamous Cell Carcinoma

“…A previous study showed that silencing arachidonate lipoxygenase E3 (ALOXE3) in HT-1080 cells made cells resistant to erastin, which supports that ALOXE3 is required for erastin-induced ferroptosis ( Yang et al, 2016 ). Another study revealed that ALOXE3 is markedly downregulated in human glioblastoma (GBM) and that ALOXE3 deficiency renders GBM cells resistant to ferroptosis, promoting GBM cell survival ( Yang et al, 2021 ). Gao et al found that knockdown of SLC38A1 markedly blocked ferroptosis, suggesting that SLC38A1 positively regulates ferroptosis ( Gao et al, 2016 ).…”

Ferroptosis in Cancer Progression: Role of Noncoding RNAs

“…In addition, miR-137 inhibited glutaminolysis by suppressing the glutamine transporter solute carrier family 1 membrane 5 (SLC1A5) [81]. Moreover, several studies have revealed that ncRNAs can induce lipid peroxidation by regulating the translation of the fundamental enzymes for the biosynthesis of unsaturated phospholipids, such as ACSL4 [96,97], ALOX15 [80], and ALOXE3 [98]. In summary, ncRNAs play crucial roles in many biological processes of ferroptosis occurrence and development.…”

“…Hence, it is essential to explore the regulatory mechanism of glioma and some novel therapeutic methods. Recently, some studies have reported that some ncRNAs play important roles in inhibiting glioma via ferroptosis [76,98]. Xinzhi Yang [98] revealed that miR-18a accelerated glioblastoma advancement by directly inhibiting ALOXE3-mediated ferroptotic and antimigration activities.…”