Opposed Interplay between IDH1 Mutations and the WNT/β-Catenin Pathway: Added Information for Glioma Classification

Vallée, Alexandre; Lecarpentier, Yves; Vallée, Jean-Noël

doi:10.3390/biomedicines9060619

Cited by 9 publications

(7 citation statements)

References 232 publications

(290 reference statements)

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“…Altered Wnt signaling can ultimately result in dysregulation of differentiation and morphogenesis to help drive tumor progression 42,[67][68][69][70] . Hypermethylation and/or down-regulation of Wnt signaling modulators and pathway members to result in aberrant Wnt signaling has been reported as a consequence of IDH1 R132H expression by us 9 and others 54,[71][72][73] . Hypermethylation of Wnt signaling in general has been implicated in a variety of cancers 68,74 , including hypermethylation of WNT9A and FZD9 genes 67,75 .…”

Section: Discussionmentioning

confidence: 82%

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

Adam,

Robinson,

Schwartz

et al. 2024

Preprint

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Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces the oncometabolite D-2-hydroxyglutarate (D2HG), which can inhibit DNA and histone demethylases to drive tumorigenesis via epigenetic changes. Though heterozygous point mutations in patients primarily affect residue R132, there are myriad D2HG-producing mutants that display unique catalytic efficiency of D2HG production. Here, we show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of IDH1 R132Q in cellular and mouse xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H-expressing models. Reduced representation bisulfite sequencing (RRBS) analysis of xenograft tumors shows expression of IDH1 R132Q relative to R132H leads to hypermethylation patterns in pathways associated with DNA damage. Transcriptome analysis indicates that the IDH1 R132Q mutation has a more aggressive pro-tumor phenotype, with members of EGFR, Wnt, and PI3K signaling pathways differentially expressed, perhaps through non-epigenetic routes. Together, these data suggest that the catalytic efficiency of IDH1 mutants modulate D2HG levels in cellular and in vivo models, resulting in unique epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

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Section: Discussionmentioning

confidence: 82%

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

Adam,

Robinson,

Schwartz

et al. 2024

Preprint

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“…Major advances in cancer genetics have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including GB [30,31]. More than 90% of the mutations in IDH1 are R132H, which has been associated with significantly improved prognosis and longer progression-free and overall survival [32,33].…”

Section: Discussionmentioning

confidence: 99%

DKK3 Expression in Glioblastoma: Correlations with Biomolecular Markers

Caffo,

Casili,

Caruso

et al. 2024

IJMS

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Glioblastoma is the most common malignant primary tumor of the CNS. The prognosis is dismal, with a median survival of 15 months. Surgical treatment followed by adjuvant therapies such as radiotherapy and chemotherapy characterize the classical strategy. The WNT pathway plays a key role in cellular proliferation, differentiation, and invasion. The DKK3 protein, capable of acting as a tumor suppressor, also appears to be able to modulate the WNT pathway. We performed, in a series of 40 patients, immunohistochemical and Western blot evaluations of DKK3 to better understand how the expression of this protein can influence clinical behavior. We used a statistical analysis, with correlations between the expression of DKK3 and overall survival, age, sex, Ki-67, p53, and MGMT and IDH status. We also correlated our data with information included in the cBioPortal database. In our analyses, DKK3 expression, in both immunohistochemistry and Western blot analyses, was reduced or absent in many cases, showing downregulation. To date, no clinical study exists in the literature that reports a potential correlation between IDH and MGMT status and the WNT pathway through the expression of DKK3. Modulation of this pathway through the expression of DKK3 could represent a new tailored therapeutic strategy in the treatment of glioblastoma.

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“…IDH1-WT GBM, accounting for almost 90% of all GBM, features with high WNT/β-catenin pathway activity 29 . Disrupting β-catenin stability has been a major strategy in inactivating WNT signaling to prevent the malignant behavior of GBM 30 , 31 .…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

Li,

Bao,

Zheng

et al. 2023

Theranostics

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Background: Elucidation of the mechanism of ubiquitation has led to novel ways to treat glioblastoma (GBM). A tripartite motif (TRIM) protein mediates a reversible, stringent ubiquitation which is closely related to glioma malignancy. This study intends to screen the most vital and abnormal regulating component of the tripartite motif protein and to explore its underlying mechanisms. Methods: TRIM21 is identified as an important oncogene that accelerates the progression of glioma cell through database in a multidimensional way and this is confirmed in human samples and cells. Tandem Mass Tags (TMT) and MS analysis are performed to discover the substrates of TRIM21.The underlying mechanisms are further investigated by CO-IP, luciferase reporter assays and gain and loss of function assays. In vivo treatment with siRNA is applied to evaluate the therapeutic significance of TRIM21. Result: We screened a panel of TRIM proteins and identified TRIM21, a E3 ubiquitin-protein ligase and autoantigen, as well as a prognostic biomarker for GBM. Functionally, high expression of wild-type TRIM21 accelerates tumor progression in vitro and in vivo , whereas TRIM21 mutants, including one with a critical RING-finger deletion, do not. Mechanistically, TRIM21 stimulates K63-linked ubiquitination and subcellular translocation of active β-catenin from the cytoplasm to the nucleus. Moreover, TRIM21 forms a complex with the β-catenin upstream regulator, TIF1γ, in the nucleus and accelerated its degradation by inducing K48-linked ubiquitination at K5 site, consequently increasing further nuclear β-catenin presence. Endogenous TRIM21 levels are found to be inversely correlated with TIF1γ but positively correlated with β-catenin in glioma tissue microarray experiments. Furthermore, direct injection of TRIM21 small interfering RNA (siRNA) into U87 cell-derived tumors (in vivo treatment with siRNA) is proved to inhibit tumor growth in nude mice. Conclusion: This work suggests that TRIM21/TIF1γ/β-catenin axis is involved in the progression of human GBM. TRIM21 is a promising therapeutic and prognostic biomarker for glioma with hyperactive β-catenin.

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Opposed Interplay between IDH1 Mutations and the WNT/β-Catenin Pathway: Added Information for Glioma Classification

Cited by 9 publications

References 232 publications

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models

DKK3 Expression in Glioblastoma: Correlations with Biomolecular Markers

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate β-catenin signaling in glioblastoma

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