Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells

Tao, Weiwei; Lei, Hong; Luo, Wenlong; Huang, Zhi; Ling, Peng; Guo, Mengyue; Wan, Lihao; Zhai, Kui; Huang, Qian; Wu, Qiulian; Xu, Shutong; Zeng, Liang; Wang, Xiuxing; Dong, Zhiqiang; Rich, Jeremy N; Bao, Shideng

doi:10.1093/neuonc/noac272

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…GBMs resistance to treatment and its challenging prognosis is mostly owing to the high fraction of GSC and the resulting intra-tumor heterogeneity from genetic, epigenetic, developmental, and microenvironmental factors [39]. Research shows that GSCs are essential for tumor initiation, invasion, angiogenesis, immune suppression, microenvironment maintenance, and treatment resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Research shows that GSCs are essential for tumor initiation, invasion, angiogenesis, immune suppression, microenvironment maintenance, and treatment resistance. Therefore, exploring the molecular pathways that trigger GSC proliferation and tumor growth has the potential to offer new insights into the aggressive nature of GBM and uncover novel therapeutic targets [39].…”

Section: Discussionmentioning

confidence: 99%

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Interaction of NF-κB and FOSL1 drives glioma stemness

Ramar,

Guo,

Hudson

et al. 2024

Cell. Mol. Life Sci.

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Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor; GBM’s inevitable recurrence suggests that glioblastoma stem cells (GSC) allow these tumors to persist. Our previous work showed that FOSL1, transactivated by the STAT3 gene, functions as a tumorigenic gene in glioma pathogenesis and acts as a diagnostic marker and potential drug target in glioma patients. Accumulating evidence shows that STAT3 and NF-κB cooperate to promote the development and progression of various cancers. The link between STAT3 and NF-κB suggests that NF-κB can also transcriptionally regulate FOSL1 and contribute to gliomagenesis. To investigate downstream molecules of FOSL1, we analyzed the transcriptome after overexpressing FOSL1 in a PDX-L14 line characterized by deficient FOSL1 expression. We then conducted immunohistochemical staining for FOSL1 and NF-κB p65 using rabbit polyclonal anti-FOSL1 and NF-κB p65 in glioma tissue microarrays (TMA) derived from 141 glioma patients and 15 healthy individuals. Next, mutants of the human FOSL1 promoter, featuring mutations in essential binding sites for NF-κB were generated using a Q5 site-directed mutagenesis kit. Subsequently, we examined luciferase activity in glioma cells and compared it to the wild-type FOSL1 promoter. Then, we explored the mutual regulation between NF-κB signaling and FOSL1 by modulating the expression of NF-κB or FOSL1. Subsequently, we assessed the activity of FOSL1 and NF-κB. To understand the role of FOSL1 in cell growth and stemness, we conducted a CCK-8 assay and cell cycle analysis, assessing apoptosis and GSC markers, ALDH1, and CD133 under varying FOSL1 expression conditions. Transcriptome analyses of downstream molecules of FOSL1 show that NF-κB signaling pathway is regulated by FOSL1. NF-κB p65 protein expression correlates to the expression of FOSL1 in glioma patients, and both are associated with glioma grades. NF-κB is a crucial transcription factor activating the FOSL1 promoter in glioma cells. Mutual regulation between NF-κB and FOSL1 contributes to glioma tumorigenesis and stemness through promoting G1/S transition and inhibiting apoptosis. Therefore, the FOSL1 molecular pathway is functionally connected to NF-κB activation, enhances stemness, and is indicative that FOSL1 may potentially be a novel GBM drug target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interaction of NF-κB and FOSL1 drives glioma stemness

Ramar,

Guo,

Hudson

et al. 2024

Cell. Mol. Life Sci.

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Sabotaging the protein factory to overcome glioma stem cell resistance

2023

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Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies

Agosti,

Antonietti,

Ius

et al. 2024

IJMS

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Gliomas’ aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells’ distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.

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Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells

Cited by 3 publications

References 45 publications

Interaction of NF-κB and FOSL1 drives glioma stemness

Interaction of NF-κB and FOSL1 drives glioma stemness

Sabotaging the protein factory to overcome glioma stem cell resistance

Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies

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