FOXM1

FOXM1 is known to play a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases.{{cite journal | vauthors = Wierstra I, Alves J | title = FOXM1, a typical proliferation-associated transcription factor | journal = Biol. Chem. | volume = 388 | issue = 12 | pages = 1257–74 | date = December 2007 | pmid = 18020943 | doi = 10.1515/BC.2007.159 | s2cid = 19721737 }} FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid cardiomyocytes and hepatocytes, highlighting the role of FOXM1 in mitotic division. More recently a study using transgenic/knockout mouse embryonic fibroblasts and human osteosarcoma cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as Plk1, cyclin B2, Nek2 and CENPF, and plays an important role in maintenance of chromosomal segregation and genomic stability.{{cite journal | vauthors = Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH | title = FoxM1 is required for execution of the mitotic programme and chromosome stability | journal = Nat. Cell Biol. | volume = 7 | issue = 2 | pages = 126–36 | date = February 2005 | pmid = 15654331 | doi = 10.1038/ncb1217 | s2cid = 11732068 }}

FOXM1 gene is now known as a human proto-oncogene.{{cite journal | vauthors = Myatt SS, Lam EW | title = The emerging roles of forkhead box (Fox) proteins in cancer | journal = Nat. Rev. Cancer | volume = 7 | issue = 11 | pages = 847–59 | date = November 2007 | pmid = 17943136 | doi = 10.1038/nrc2223 | s2cid = 1330189 }} Abnormal upregulation of FOXM1 is involved in the oncogenesis of basal cell carcinoma, the most common human cancer worldwide.{{cite journal | vauthors = Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG | title = FOXM1 is a downstream target of Gli1 in basal cell carcinomas | journal = Cancer Res. | volume = 62 | issue = 16 | pages = 4773–80 | date = 15 August 2002 | pmid = 12183437 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12183437 }} The upregulation of both FOXM1 and its targets has been found in the majority of solid human cancers {{cite journal | vauthors = Pozzobon D, Bellezza A, Giorgi FM | title = Pan-Cancer Upregulation of the FOXM1 Transcription Factor | journal = Genes | volume = 16 | issue = 1 | pages = 56–66 | date = January 2025 | pmid = 39858603 | pmc = 11765198 | doi = 10.3390/genes16010056 | doi-access = free }} including liver,{{cite journal | vauthors = Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH | title = Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor | journal = Genes Dev. | volume = 18 | issue = 7 | pages = 830–50 | date = April 2004 | pmid = 15082532 | pmc = 387422 | doi = 10.1101/gad.1200704 }} breast,{{cite journal | vauthors = Wonsey DR, Follettie MT | title = Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe | journal = Cancer Res. | volume = 65 | issue = 12 | pages = 5181–9 | date = June 2005 | pmid = 15958562 | doi = 10.1158/0008-5472.CAN-04-4059 | doi-access = free }} lung,{{cite journal | vauthors = Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV | title = The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer | journal = Cancer Res. | volume = 66 | issue = 4 | pages = 2153–61 | date = February 2006 | pmid = 16489016 | doi = 10.1158/0008-5472.CAN-05-3003 | doi-access = free }} prostate,{{cite journal | vauthors = Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH | title = Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice | journal = Cancer Res. | volume = 66 | issue = 3 | pages = 1712–20 | date = February 2006 | pmid = 16452231 | pmc = 1363687 | doi = 10.1158/0008-5472.CAN-05-3138 }} cervix of uterus,{{cite journal | vauthors = Chan DW, Yu SY, Chiu PM, Yao KM, Liu VW, Cheung AN, Ngan HY | title = Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis | journal = J. Pathol. | volume = 215 | issue = 3 | pages = 245–52 | date = July 2008 | pmid = 18464245 | doi = 10.1002/path.2355 | s2cid = 30137454 }} colon,{{cite journal | vauthors = Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S | title = Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer | journal = Surgery | volume = 139 | issue = 5 | pages = 665–70 | date = May 2006 | pmid = 16701100 | doi = 10.1016/j.surg.2005.10.012 }} and brain.{{cite journal | vauthors = Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S | title = FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells | journal = Cancer Res. | volume = 66 | issue = 7 | pages = 3593–602 | date = April 2006 | pmid = 16585184 | doi = 10.1158/0008-5472.CAN-05-2912 | citeseerx = 10.1.1.321.4506 }}

There are three FOXM1 isoforms in humans, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional repressor whereas the remaining isoforms (B and C) are both transcriptional activators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.

The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.{{cite journal | vauthors = Teh MT, Gemenetzidis E, Chaplin T, Young BD, Philpott MP | title = Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes | journal = Mol. Cancer | volume = 9 | pages = 45 | year = 2010 | pmid = 20187950 | pmc = 2907729 | doi = 10.1186/1476-4598-9-45 | doi-access = free }}

FOXM1 overexpression is involved in early events of carcinogenesis in head and neck squamous cell carcinoma. It has been shown that nicotine exposure directly activates FOXM1 activity in human oral keratinocytes and induced malignant transformation.{{cite journal | vauthors = Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT | title = FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation | journal = PLOS ONE| volume = 4 | issue = 3 | pages = e4849 | year = 2009 | pmid = 19287496 | pmc = 2654098 | doi = 10.1371/journal.pone.0004849 | bibcode = 2009PLoSO...4.4849G | editor1-last = Jin | editor1-first = Dong-Yan | doi-access = free }}

A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system – a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.{{cite journal | vauthors = Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT | title = Induction of human epithelial stem/progenitor expansion by FOXM1 | journal = Cancer Res. | volume = 70 | issue = 22 | pages = 9515–26 | year = 2010 | pmid = 21062979 | pmc = 3044465 | doi = 10.1158/0008-5472.CAN-10-2173 }}

Given the role in progenitor/stem cells expansion, FOXM1 has been shown to modulate the epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like epigenome. A number of new epigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to represent epigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.{{cite journal | vauthors = Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW, Waseem A, Hutchison IL | title = FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma | journal = PLOS ONE| volume = 7 | issue = 3 | pages = e34329 | year = 2012 | pmid = 22461910 | pmc = 3312909 | doi = 10.1371/journal.pone.0034329 | bibcode = 2012PLoSO...734329T | doi-access = free }}

FOXM1 has been shown to interact with Cdh1.{{cite journal | vauthors = Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH | title = FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner | journal = Cell Cycle | volume = 7 | issue = 17 | pages = 2720–6 | date = Sep 2008 | pmid = 18758239 | doi = 10.4161/cc.7.17.6580 | doi-access = free }}

• FOX proteins

{{reflist}}

• {{MeshName|FOXM1+protein,+human}}

{{NLM content}}

{{Transcription factors|g3}}

{{DEFAULTSORT:Foxm1}}

Category:Forkhead transcription factors