Impact of epigenetic reprogramming on antitumor immune responses in glioma

McClellan, Brandon L.; Haase, Santiago; Núñez, Felipe J.; Alghamri, Mahmoud S.; Dabaja, Ali; Löwenstein, Pedro R.; Castro, Maria G.

doi:10.1172/jci163450

Cited by 29 publications

(29 citation statements)

References 134 publications

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“…Glioma is a highly aggressive and deadly form of brain cancer, characterized by complex genetic and epigenetic alterations that contribute to its pathogenesis and progression. 16,17 Epigenetic modifications, such as DNA methylation, play a crucial role in regulating gene expression and cellular processes in glioma. In this study, we aimed to explore the role of F-box protein 32 (FBXO32) in glioma progression and its regulatory interactions with DNA methyltransferase-1 (DNMT1) and S-phase kinase-associated protein 1 (SKP1).…”

Section: Discussionmentioning

confidence: 99%

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

Quan,

2023

Environmental Toxicology

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Glioma, a prevalent and serious form of brain cancer, is associated with dysregulation of DNA methylation, where DNA methyltransferase‐1 (DNMT1) plays a significant role in glioma progression. However, the involvement of F‐box protein 32 (FBXO32) in glioma and its regulation by DNMT1‐mediated methylation remain poorly understood. In this study, we investigated FBXO32 expression in glioma cells with high DNMT1 expression using the online dataset and correlated it with patient survival. Then impact of elevated FBXO32 expression on cell proliferation, migration, and invasion was evaluated, along with the examination of EMT‐related proteins. Furthermore, a xenograft model established by injecting glioma cells stably transfected with FBXO32 was used to evaluate tumor growth, volume, and weight. The ChIP assay was employed to study the interaction between DNMT1 and the FBXO32 promoter, revealing that DNMT1 negatively correlated with FBXO32 expression in glioma cells and promoted FBXO32 promoter methylation. Moreover, we investigated the interaction between FBXO32 and SKP1 using Co‐IP and GST pulldown assays, discovering that FBXO32 acts as an E3 ubiquitin ligase and promotes SKP1 ubiquitination, leading to its degradation. Interestingly, our findings demonstrated that high FBXO32 expression was associated with improved overall survival in glioma patients. Knockdown of DNMT1 in glioma cells increased FBXO32 expression and suppressed malignant phenotypes, suggesting that FBXO32 functions as a tumor suppressor in glioma. In conclusion, this study reveals a novel regulatory mechanism involving DNMT1‐mediated FBXO32 expression in glioma cells, where FBXO32 acts as an E3 ubiquitin ligase to degrade SKP1 via ubiquitination. This FBXO32‐mediated regulation of SKP1 activity contributes to the progression of glioma cells. These findings provide important insights into the molecular mechanisms underlying glioma progression and may hold promise for the development of targeted therapies for glioma patients.

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Section: Discussionmentioning

confidence: 99%

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

Quan,

2023

Environmental Toxicology

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“…GSCs are maintained within perivascular collagen-rich niches (Motegi et al 2014;Calabrese et al 2007), and are known to evade antitumor immune responses through various mechanisms, including downregulation of MHC class I, induction of quiescence, and other mechanisms that promote immune tolerance (McClellan et al 2023). Therefore, we hypothesized that GBM P-FB cells can modulate anti-tumor immune responses through maintenance of GSCs in the perivascular niche.…”

Section: Perivascular Fibroblasts Promote Immune-evasive Stem-like Ca...mentioning

confidence: 99%

Pan-cancer transcriptomic analysis of CNS tumor stroma identifies a population of perivascular fibroblasts that predict poor immunotherapy response in glioblastoma patients

Zarodniuk

Steele

Lü

et al. 2023

Preprint

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Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease. We found that CNS lesions – glioblastoma in particular – can be divided into two ECM-based subtypes (ECMhi and ECMlo) that are influenced by the presence of perivascular cells resembling cancer-associated fibroblasts (CAFs). We show that perivascular fibroblasts activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote an immune-evasive, stem-like cancer cell phenotype. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors. We provide insights into novel stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma, and discuss how targeting these perivascular fibroblasts may prove an effective approach to improving treatment response and patient survival in a variety of CNS tumors.

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“…2 The most prevalent subtype, glioblastoma (GBM), accounts for 57.7% of gliomas. 3 Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioma patients and the only chemotherapeutic drug that has been confirmed to significantly prolong overall survival (OS), 4 yet the median survival after receiving TMZ treatment combined with surgical resection, radiotherapy, 5,6 targeted therapy, and supportive care is only 14-16 months for GBM patients, [7][8][9][10] with a 5-year recurrence rate as high as 90%. 11 The reason for this low survival rate and high recurrence rate is largely due to its invasive behavior and resistance to current treatments, including TMZ, 7 owing to its cellular and molecular heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

“…Glioma accounts for approximately 81% of primary brain tumors 1 ; it has a high incidence rate and a poor prognosis 2 . The most prevalent subtype, glioblastoma (GBM), accounts for 57.7% of gliomas 3 . Temozolomide (TMZ) is a first‐line chemotherapeutic agent for glioma patients and the only chemotherapeutic drug that has been confirmed to significantly prolong overall survival (OS), 4 yet the median survival after receiving TMZ treatment combined with surgical resection, radiotherapy, 5,6 targeted therapy, and supportive care is only 14–16 months for GBM patients, 7–10 with a 5‐year recurrence rate as high as 90% 11 .…”

Section: Introductionmentioning

confidence: 99%

Interferon‐γ inducible protein 30 promotes the epithelial–mesenchymal transition‐like phenotype and chemoresistance by activating EGFR/AKT/GSK3β/β‐catenin pathway in glioma

Chen

et al. 2023

CNS Neurosci Ther

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AimsPrevious studies have indicated that IFI30 plays a protective role in human cancers. However, its potential roles in regulating glioma development are not fully understood.MethodsPublic datasets, immunohistochemistry, and western blotting (WB) were used to evaluate the expression of IFI30 in glioma. The potential functions and mechanisms of IFI30 were examined by public dataset analysis; quantitative real‐time PCR; WB; limiting dilution analysis; xenograft tumor assays; CCK‐8, colony formation, wound healing, and transwell assays; and immunofluorescence microscopy and flow cytometry.ResultsIFI30 was significantly upregulated in glioma tissues and cell lines compared with corresponding controls, and the expression level of IFI30 was positively associated with tumor grade. Functionally, both in vivo and in vitro evidence showed that IFI30 regulated the migration and invasion of glioma cells. Mechanistically, we found that IFI30 dramatically promoted the epithelial–mesenchymal transition (EMT)‐like process by activating the EGFR/AKT/GSK3β/β‐catenin pathway. In addition, IFI30 regulated the chemoresistance of glioma cells to temozolomide directly via the expression of the transcription factor Slug, a key regulator of the EMT‐like process.ConclusionThe present study suggests that IFI30 is a regulator of the EMT‐like phenotype and acts not only as a prognostic marker but also as a potential therapeutic target for temozolomide‐resistant glioma.

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Impact of epigenetic reprogramming on antitumor immune responses in glioma

Cited by 29 publications

References 134 publications

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

Pan-cancer transcriptomic analysis of CNS tumor stroma identifies a population of perivascular fibroblasts that predict poor immunotherapy response in glioblastoma patients

Interferon‐γ inducible protein 30 promotes the epithelial–mesenchymal transition‐like phenotype and chemoresistance by activating EGFR/AKT/GSK3β/β‐catenin pathway in glioma

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