FOXM1 in meningioma

Data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signaling pathways in meningioma progression and a promising therapeutic target for aggressive meningioma 1) 2).

Radiologic and radiomic predictors of adverse meningioma outcomes were significantly associated with molecular markers of aggressive meningioma biologies, such as somatic mutation burden, DNA methylation status, and FOXM1 expression. Integrated prognostic models combining clinical, radiologic, and radiomic features demonstrated improved accuracy for meningioma grade, LF, and OS (area under the curve 0.78, 0.75, and 0.78, respectively) compared to models based on clinical features alone 3).

Wu et al. aimed to uncover their functions and correlation in malignant meningioma.

Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect FOXM1 expression in malignant meningioma and adjacent tissues. The viability, proliferation, apoptosis, and tube formation of meningioma IOMM-Lee and CH157-MN cells transfected with overexpressed FOXM1 were examined with MTT assay, clone formation assay, flow cytometry and tube formation assay, respectively. The expressions of AHR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in meningioma and adjacent tissues were detected using qRT-PCR, and the correlation of AHR with FOXM1 was analyzed with Pearson's correlation analysis. Western blot was conducted for measuring the expressions of vascular endothelial growth factor A (VEGFA), AHR and CYP1A1. The cell viability, proliferation, apoptosis and tube formation capability were further determined after treatment with StemRegenin 1 (SR1) (an AHR signaling pathway inhibitor), and transfected with or without overexpressed FOXM1.

FOXM1, AHR and CYP1A1 expressions were upregulated in malignant meningioma tissues. Overexpressed FOXM1 promoted meningioma cell viability, proliferation, tube formation, upregulated expressions of AHR, CYP1A1 and VEGFA, and inhibited the cell apoptosis. AHR was positively correlated with FOXM1. SR1 suppressed meningioma cell growth and the AHR signaling pathway, and also reversed the active effect of FOXM1 on meningioma cells.

FOXM1 may promote malignant meningioma via the AHR signaling pathway, which improved the current understanding of the role of FOXM1 in meningioma 4).

Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element-binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling 5).

DNA methylation patterns delineate clinically relevant subgroups for meningioma classification. Paramasivam et al., previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant.

They set out to identify subgroup-specific mutational patterns and gene regulation. Whole-genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super-enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging homologous recombination repair (HRR) as a novel therapeutic target 6).

Kim H, Park KJ, Ryu BK, Park DH, Kong DS, Chong K, Chae YS, Chung YG, Park SI, Kang SH. Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression. Neuropathol Appl Neurobiol. 2020 Feb;46(2):125-141. doi: 10.1111/nan.12571. Epub 2019 Jul 5. PMID: 31179553.
Vasudevan HN, Braunstein SE, Phillips JJ, Pekmezci M, Tomlin BA, Wu A, Reis GF, Magill ST, Zhang J, Feng FY, Nicholaides T, Chang SM, Sneed PK, McDermott MW, Berger MS, Perry A, Raleigh DR. Comprehensive Molecular Profiling Identifies FOXM1 as a Key Transcription Factor for Meningioma Proliferation. Cell Rep. 2018 Mar 27;22(13):3672-3683. doi: 10.1016/j.celrep.2018.03.013. PMID: 29590631.
Morin O, Chen WC, Nassiri F, Susko M, Magill ST, Vasudevan HN, Wu A, Vallières M, Gennatas ED, Valdes G, Pekmezci M, Alcaide-Leon P, Choudhury A, Interian Y, Mortezavi S, Turgutlu K, Bush NAO, Solberg TD, Braunstein SE, Sneed PK, Perry A, Zadeh G, McDermott MW, Villanueva-Meyer JE, Raleigh DR. Integrated models incorporating radiologic and radiomic features predict meningioma grade, local failure, and overall survival. Neurooncol Adv. 2019 May-Dec;1(1):vdz011. doi: 10.1093/noajnl/vdz011. Epub 2019 Aug 28. PMID: 31608329; PMCID: PMC6777505.
Wu Q, Zheng J, Dou C, Qi S. Forkhead Box M1 promotes the growth and tube formation of human malignant meningioma cells via the aryl hydrocarbon receptor signaling pathway. Folia Neuropathol. 2020;58(3):223-236. doi: 10.5114/fn.2020.100065. PMID: 33099292.
Deng J, Hua L, Han T, Tian M, Wang D, Tang H, Sun S, Chen H, Cheng H, Zhang T, Xie Q, Wan L, Zhu H, Gong Y. The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations. Neurooncol Adv. 2020 Feb 22;2(1):vdz055. doi: 10.1093/noajnl/vdz055. PMID: 32642722; PMCID: PMC7212891.
Paramasivam N, Hübschmann D, Toprak UH, Ishaque N, Neidert M, Schrimpf D, Stichel D, Reuss D, Sievers P, Reinhardt A, Wefers AK, Jones DTW, Gu Z, Werner J, Uhrig S, Wirsching HG, Schick M, Bewerunge-Hudler M, Beck K, Brehmer S, Urbschat S, Seiz-Rosenhagen M, Hänggi D, Herold-Mende C, Ketter R, Eils R, Ram Z, Pfister SM, Wick W, Weller M, Grossmann R, von Deimling A, Schlesner M, Sahm F. Mutational patterns and regulatory networks in epigenetic subgroups of meningioma. Acta Neuropathol. 2019 May 8. doi: 10.1007/s00401-019-02008-w. [Epub ahead of print] PubMed PMID: 31069492.
  • foxm1_in_meningioma.txt
  • Last modified: 2020/10/26 09:03
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