HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350.

Tumor suppression by inducing NCOA4-mediated ferroptosis has been shown to be feasible in a variety of tumors, including gliomas. However, the regulatory mechanism of ferroptosis induced by NCOA4 in glioma has not been studied deeply. HECW1 and ZNF350 are involved in the biological processes of many tumors, but their specific effects and mechanisms on glioma are still unclear. In this study, we found that HECW1 decreased the survival rate of glioma cells and enhanced iron accumulation, lipid peroxidation, whereas ZNF350 showed the opposite effect. Mechanistically, HECW1 directly regulated the ubiquitination and degradation of ZNF350, eliminated the transcriptional inhibition of NCOA4 by ZNF350, and ultimately activated NCOA4-mediated iron accumulation, lipid peroxidation, and ferroptosis. We demonstrate that HECW1 induces ferroptosis and highlight the value of HECW1 and ZNF350 in the prognostic evaluation of patients with glioma. We also elucidate the mechanisms underlying the HECW1/ZNF350/NCOA4 axis and its regulation of ferroptosis. Our findings enrich the understanding of ferroptosis and provide potential treatment options for glioma patients.

TUG1/MAZ/FTH1 Axis Attenuates the Antiglioma Effect of Dihydroartemisinin by Inhibiting Ferroptosis.

Glioma is the most common primary intracranial malignant tumor in the brain. Currently, due to the limited treatment methods, the clinical outcome of patients with standard surgery combined with radiotherapy and chemotherapy is not satisfactory. Therefore, we urgently need to develop effective drugs to solve this problem. As a semisynthetic derivative of artemisinin, dihydroartemisinin (DHA) has been proved to have antitumor activity in glioma, which can induce apoptosis and inhibit the proliferation, migration, and invasion of glioma cells. In recent years, ferroptosis has been identified as another antitumor mechanism of DHA. Researchers have shown that DHA could promote ferroptosis in glioma cells. However, the specific molecular mechanisms of ferroptosis induced by DHA need more exploration. In this study, we found DHA could induce ferroptosis with ROS production and lipid peroxidation in glioma cells. Low expression of GPX4 and high expression of HMOX1 were identified in DHA treated glioma cells. Surprisingly, we found FTH1, a negative regulator of ferroptosis, upregulated in DHA treated glioma cells. It indicated that there should be some mechanisms that may cause ferroptosis attenuation in DHA treated glioma cells. For the first time, we confirmed that MYC-associated zinc finger protein (MAZ) could actively regulate FTH1 by binding to FTH1 promoter by CHIP assay. MAZ was further identified as the direct target of long noncoding RNA (lncRNA) TUG1 through luciferase assay. Downregulated expression of TUG1 and upregulated expression of MAZ were identified in DHA treated glioma cells. TUG1 overexpression or inhibition of FTH1 expression could enhance the antiglioma effect of DHA in vitro and in vivo, providing a promising strategy to enhance the antitumor effect of DHA in glioma.

Trametinib Inhibits the Growth and Aerobic Glycolysis of Glioma Cells by Targeting the PKM2/c-Myc Axis.

Gliomas are primary tumors originating from glial progenitor cells. Traditional treatments, including surgery, radiotherapy, and chemotherapy, have many limitations concerning the prognosis of patients with gliomas. Therefore, it is important to find novel drugs to effectively treat gliomas. Trametinib has been shown to inhibit the MAPK pathway and regulate its downstream extracellular-related kinases. It has widely been used in the treatment of BRAF V600E mutant metastatic melanomas. Previous studies found that trametinib can improve the prognosis of patients with melanoma brain metastases. In this study, we investigated the therapeutic effects of trametinib on gliomas in vivo and in vitro. We found that trametinib can inhibit proliferation, migration, and invasion of glioma cells, while inducing apoptosis of glioma cells. Specifically, trametinib can suppress both the expression of PKM2 in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of ERK1/2 expression. However, inhibition of these cellular effects and intracellular glycolysis levels were reversed by overexpressing PKM2 in glioma cells. We also found inhibition of c-myc with trametinib treatment, but its expression could be increased by overexpressing PKM2. Interestingly, when PKM2 was overexpressed but c-myc silenced, we found that the initial inhibition of cellular effects and glycolysis levels by trametinib were once again restored. These inhibitory effects were also confirmed in vivo: trametinib inhibited the growth of the transplanted glioma cell tumor, whereas PKM2 overexpression and c-myc silencing restored the inhibition of trametinib on the growth of the transplanted tumor. In conclusion, these experimental results showed that trametinib may inhibit the growth and intracellular glycolysis of glioma cells by targeting the PKM2/c-myc pathway.