foxm1

FOXM1

Forkhead Box M1 (FOXM1), is a FOX protein, well demonstrated to be critical for proliferation, apoptosis, migration and invasion of human cancer 1).

It is encoded by the FOXM1 gene.

FOXM1 has been awarded the Molecule of the Year 2010 for its growing potential as a target for cancer diagnosis and therapies.


Temozolomide resistance is considered to be one of the major reasons responsible for glioblastoma treatment failure. CXCL12/CXCR4 has been demonstrated to be involved in cell proliferation, cell migration, cell invasion, angiogenesis, and radioresistance in glioblastoma (GBM). However, its role in TMZ resistance in GBM is unknown. Wang et al. aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. They found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. This study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM 2).


Silencing of FoxM1 could reverse TGF-β1-induced invasion and epithelial-mesenchymal transition (EMT) of endometriotic epithelial cells (EECs) 3).


FoxM1 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity 4) , by enhancing MMP-2 gene transcription and thus tumor-cell invasion 5) , enhancing VEGF gene transcription and thus tumor angiogenesis 6) , in cooperation with p53 and pRB inhibition in NHA cells, promotes astrocyte transformation and GBM formation through multiple mechanisms 7).

FoxM1-β-catenin interaction controls Wnt target gene expression, is required for glioma formation, and represents a mechanism for canonical Wnt signaling during tumorigenesis 8).

Results indicate that FoxM1 is regulated by HSF1 and is critical for HSF1-mediated heat shock response. Dai et al. demonstrated a novel mechanism of stress resistance controlled by HSF1 and a new HSF-FoxM1 connection that mediates cellular thermotolerance 9).


Findings provide both clinical and mechanistic evidences that FoxM1 contributes to glioma development by directly up-regulating Anxa1 expression 10).


Results fadd a new FoxM1-Sirt1 connection that mediates cell proliferation in glioma 11).


Liu et al. found that the oncogenic transcription factor FOXM1 was also downregulated in PHDGH-silenced glioma cells. Using LC/LC MS analysis, we identified PHGDH as a novel binding partner of FOXM1. PHGDH interacted with and stabilized FOXM1 at the protein level, promoting the proliferation, invasion and tumorigenicity of glioma cells. Our data identified PHGDH as a potential prognostic marker of glial brain tumors and identified a non-metabolic role for PHGDH in glioma tumorigenesis, providing a novel angle of targeting the PHGDH-FOXM1 axis in future brain tumor therapy 12).


CXCL12 promotes GBM cell invasion in part by increasing the expression of FOXM1, which is mediated in part by a PI3K/AKT-dependent mechanism in vitro 13).


Targeting the FoxM1-Rad51 axis may be an effective method to reverse TMZ resistance in recurrent GBM 14).


Data suggest that targeting FOXM1 with small-molecule inhibitors results in potent antitumor activity and chemosensitizing effects in human medulloblastoma cells 15).


Overexpression of miR-216b inhibited the expression of FoxM1 in glioma cells. Rescue experiments demonstrated that co-transfection of FoxM1 lacking the 3'-untranslated region partially prevented miR‑216b-induced inhibition of glioma cell growth and invasion. In vivo studies indicated that ectopic expression of miR-216b impeded the proliferation of glioma xenograft tumours in nude mice, coupled with a decreased in FoxM1 protein expression and the percentage of Ki-67-positive tumour cells. Taken together, our results provide evidence of the suppressive activity of miR‑216b in glioma, which is largely ascribed to downregulation of FoxM1. Restoration of miR-216b may provide a novel potential therapeutic agent for glioma 16).


Elevated FOXM1 expression is associated with poor survival in most solid tumors. FOXM1 is a potential biomarker for prognosis prediction and a promising therapeutic target in human solid tumors 17).

FOXM1 in meningioma


1)
Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007 Nov;7(11):847-59. Review. PubMed PMID: 17943136.
2)
Wang S, Chen C, Li J, Xu X, Chen W, Li F. The CXCL12/CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1. J Neurol Sci. 2020 Apr 14;414:116837. doi: 10.1016/j.jns.2020.116837. [Epub ahead of print] PubMed PMID: 32334273.
3)
Zhang J, Xu Z, Dai H, Zhao J, Liu T, Zhang G. Silencing of Forkhead Box M1 Reverses Transforming Growth Factor-β1-Induced Invasion and Epithelial-Mesenchymal Transition of Endometriotic Epithelial Cells. Gynecol Obstet Invest. 2019 Apr 30:1-10. doi: 10.1159/000499625. [Epub ahead of print] PubMed PMID: 31039568.
4)
Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res. 2006 Apr 1;66(7):3593-602. PubMed PMID: 16585184.
5)
Dai B, Kang SH, Gong W, Liu M, Aldape KD, Sawaya R, Huang S. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells. Oncogene. 2007 Sep 13;26(42):6212-9. Epub 2007 Apr 2. PubMed PMID: 17404569.
6)
Zhang Y, Zhang N, Dai B, Liu M, Sawaya R, Xie K, Huang S. FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. Cancer Res. 2008 Nov 1;68(21):8733-42. doi: 10.1158/0008-5472.CAN-08-1968. PubMed PMID: 18974115; PubMed Central PMCID: PMC2597644.
7)
Dai B, Pieper RO, Li D, Wei P, Liu M, Woo SY, Aldape KD, Sawaya R, Xie K, Huang S. FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes. Cancer Res. 2010 Apr 1;70(7):2951-61. doi: 10.1158/0008-5472.CAN-09-3909. Epub 2010 Mar 23. PubMed PMID: 20332230; PubMed Central PMCID: PMC2848915.
8)
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, Sawaya R, Xie K, Yung WK, Medema RH, He X, Huang S. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011 Oct 18;20(4):427-42. doi: 10.1016/j.ccr.2011.08.016. PubMed PMID: 22014570; PubMed Central PMCID: PMC3199318.
9)
Dai B, Gong A, Jing Z, Aldape KD, Kang SH, Sawaya R, Huang S. Forkhead box M1 is regulated by heat shock factor 1 and promotes glioma cells survival under heat shock stress. J Biol Chem. 2013 Jan 18;288(3):1634-42. doi: 10.1074/jbc.M112.379362. Epub 2012 Nov 28. PubMed PMID: 23192351; PubMed Central PMCID: PMC3548473.
10)
Cheng SX, Tu Y, Zhang S. FoxM1 promotes glioma cells progression by up-regulating Anxa1 expression. PLoS One. 2013 Aug 26;8(8):e72376. doi: 10.1371/journal.pone.0072376. eCollection 2013. PubMed PMID: 23991102; PubMed Central PMCID: PMC3753245.
11)
Zhu GY, Shi BZ, Li Y. FoxM1 regulates Sirt1 expression in glioma cells. Eur Rev Med Pharmacol Sci. 2014;18(2):205-11. PubMed PMID: 24488909.
12)
Liu J, Guo S, Li Q, Yang L, Xia Z, Zhang L, Huang Z, Zhang N. Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J Neurooncol. 2013 Feb;111(3):245-55. doi: 10.1007/s11060-012-1018-x. Epub 2012 Dec 11. PubMed PMID: 23229761; PubMed Central PMCID: PMC3565087.
13)
Wang S, Zhang S, Li J, Xu X, Weng Y, Zheng M, Ouyang L, Li F. CXCL12-induced upregulation of FOXM1 expression promotes human glioblastoma cell invasion. Biochem Biophys Res Commun. 2014 Apr 25;447(1):1-6. doi: 10.1016/j.bbrc.2013.12.079. Epub 2014 Feb 19. PubMed PMID: 24561124.
14)
Zhang N, Wu X, Yang L, Xiao F, Zhang H, Zhou A, Huang Z, Huang S. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res. 2012 Nov 1;18(21):5961-71. doi: 10.1158/1078-0432.CCR-12-0039. Epub 2012 Sep 12. PubMed PMID: 22977194; PubMed Central PMCID: PMC3639123.
15)
Lin J, Zheng Y, Chen K, Huang Z, Wu X, Zhang N. Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy. Oncol Rep. 2013 Oct;30(4):1739-44. doi: 10.3892/or.2013.2654. Epub 2013 Aug 2. PubMed PMID: 23912794.
16)
Zhang T, Ma G, Zhang Y, Huo H, Zhao Y. miR-216b inhibits glioma cell migration and invasion through suppression of FoxM1. Oncol Rep. 2017 Jul 17. doi: 10.3892/or.2017.5824. [Epub ahead of print] PubMed PMID: 28731180.
17)
Li L, Wu D, Yu Q, Li L, Wu P. Prognostic value of FOXM1 in solid tumors: a systematic review and meta-analysis. Oncotarget. 2017 May 9;8(19):32298-32308. doi: 10.18632/oncotarget.15764. Review. PubMed PMID: 28427178; PubMed Central PMCID: PMC5458285.
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  • Last modified: 2020/10/26 08:37
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