CEBPB upregulates P4HA2 to promote the malignant biological behavior in IDH1 wildtype glioma. Issue 4 (11th March 2023)

• Record Type: Journal Article
• Authors: Wang, Shuai; Wu, Jingheng; Zhao, Wujun; Li, Miaomiao; Li, Shaoyi
• Is Part Of: FASEB journal. Volume 37:Issue 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-03-11
• Subjects: CEBPB -- glioma -- isocitrate dehydrogenase -- P4HA2 -- temozolomide -- ubiquitination; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202201244RRRR
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Temozolomide (TMZ), the primary drug for glioma treatment, has limited treatment efficacy. Additionally, considerable evidence shows that isocitrate dehydrogenase 1 mutation‐type (IDH1 mut) gliomas have a better response to TMZ than isocitrate dehydrogenase 1 wildtype (IDH1 wt) gliomas. Here, we aimed to identify potential mechanisms underlying this phenotype. Herein, the Cancer Genome Atlas bioinformatic data and 30 clinical samples from patients were analyzed to reveal the expression level of cytosine‐cytosine‐adenosine‐adenosine‐thymidine (CCAAT) Enhancer Binding Protein Beta (CEBPB) and prolyl 4‐hydroxylase subunit alpha 2 (P4HA2) in gliomas. Next, cellular and animal experiments, including cell proliferation, colony formation, transwell, CCK‐8, and xenograft assays, were performed to explore the tumor‐promoting effects of P4HA2 and CEBPB. Then, chromatin immunoprecipitation (ChIP) assays were used to confirm the regulatory relationships between them. Finally, a co‐immunoprecipitation (Co‐IP) assay was performed to confirm the effect of IDH1‐132H to CEBPB proteins. We found that CEBPB and P4HA2 expression was significantly upregulated in IDH1 wt gliomas and associated with poor prognosis. CEBPB knockdown inhibited the proliferation, migration, invasion, and temozolomide resistance of glioma cells and hindered the growth of glioma xenograft tumors. CEBPE, as a transcription factor, exerted its function by transcriptionally upregulating P4HA2 expression in glioma cells. Importantly, CEBPB is prone to ubiquitin‐proteasomal degradation in IDH1 R132H glioma cells. We also demonstrated that both genes are related to collagen synthesis, as confirmed by in vivo experiments. Thus, CEBPE promotes proliferation and TMZ resistance by inducing P4HA2 expression in glioma cells and offers a potential therapeutic target for glioma treatment. Abstract : CEBPB expression was significantly upregulated in IDH1 wildtype gliomas and associated with poor prognosis. Importantly, CEBPB is prone to degradation by ubiquitination in IDH1 mut glioma cells. CEBPB, as a transcription factor, promotes glioma cell proliferation and TMZ resistance by transcriptionally upregulating P4HA2 expression. In addition, both genes are related to collagen synthesis.