FOXM1

Official Full Name

forkhead box M1

Organism

Homo sapiens

GeneID

2305

Background

The protein encoded by this gene is a transcriptional activator involved in cell proliferation. The encoded protein is phosphorylated in M phase and regulates the expression of several cell cycle genes, such as cyclin B1 and cyclin D1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

Synonyms

MPP2; HFH11; HNF-3; INS-1; MPP-2; PIG29; FKHL16; FOXM1A; FOXM1B; FOXM1C; HFH-11; TRIDENT; MPHOSPH2;

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Detailed Information

Forkhead Box M1 (FOXM1) belongs to a large family of forkhead box (Fox) transcription factors. Different from the other Fox-transcription factors, FoxM1 is associated with cell proliferation and is expressed only in proliferating cells. In adult mammals, FoxM1 expression is detected mainly in the progenitor and regenerating tissues, and it is overexpressed in various human malignancies. For instance, gene expression profiles in carcinomas, including prostate, lung, breast, pancreas, ovary, colon, bladder, stomach, liver, and kidney, revealed that FoxM1 is overexpressed in all carcinomas. In addition, high expression of FoxM1 in glioblastoma correlates with the tumorigenicity of the glioma cells. Moreover, in breast cancer, overexpression of FoxM1 strongly correlates with poor prognosis. Overexpression of FoxM1 in various tumors suggests a strong dependence of the tumor cells on FoxM1, and that is explained partly by its role in cell proliferation.

FOXM1 in tumorigenesis

FOXM1 is one of a few genes shown to be upregulated during early cancer development. The involvement of FOXM1 in the onset of tumorigenesis largely relates to its role in cell cycle progression and proliferation. FOXM1 is a key regulator for G1/S and G2/M transition, and M phase progression. Apart from regulating Cdc25A expression at the G1/S checkpoint, FOXM1 also controls the transcription of Skp2 and Cks1, which are substrate-targeting subunits of the Skp1/cullin/F-box protein (SCF) complex important to the ubiquitinylation and degradation of the cyclin-dependent kinase inhibitors (CKIs), p21Waf1/Cip1 and p27Kip1. It also regulates the expression of several genes, such as Cdc25B, cyclin B, survivin, Aurora B kinase, polo-like kinase 1 (PLK1) and centromere protein A (CENPA), CENPB and CENPF, involved in G2/M transition, and the maintenance of proper chromosomal stability and segregation during mitosis. Therefore, the majority of FOXM1 depleted cells suffer delays in G2 and experience severe mitotic abnormalities upon entry into mitosis. Frequently these FOXM1-deficient cells also have mitotic spindle defects, chromosome misalignment, mitotic spindle checkpoint dysfunction as well as cytokinesis failure, leading to the cells undergoing centrosome amplication and even endoreduplication, and eventually becoming aneuploid and polyploid.

Figure 1. FOXM1 regulates crucial processes in both development and tumor progression.

FOXM1 in cancer progression

In cancer progression tumor initiation is followed by tumor promotion. Apart from its initial role in tumorigenesis, FOXM1 can also promote multiple steps of cancer progression through inducing mitogenic and survival signals, as well as promoting tumor invasion, migration and angiogenesis. There is ample evidence to implicate FOXM1 in cancer cell proliferation and growth following initial tumorigenesis. For example, cancer cell proliferation and tumor growth are significantly reduced in lung adenomas and colon adenocarcinomas carcinogenic mouse models when FoxM1 is deleted. Conversely a marked increase in the proliferation, number and size of tumors of lung adenomas, hepatocellular carcinoma (HCC), prostate and colon carcinomas was observed when mice with the FoxM1 transgene were subjected to tumor induction by carcinogens. Consistent with this, the depletion of FOXM1 by siRNA in various cancer cell lines (lung, liver, prostate, colon, breast and cervix) also results in a reduction in cell proliferation and anchorage-independent colony formation on soft agar. Moreover, the phenotypic changes that accompany FOXM1 knock-down have been shown to be associated with decreased expression of cell cycle proteins, cyclin A2, cyclin B1, and Cdc25 phosphatases, and increased expression of the cell cycle inhibitors p21Waf1/Cip1 and p27Kip1, indicating that FOXM1 is needed to sustain the cell cycle programme required for continuous cancer cell proliferation and growth.

Targeting FOXM1 in cancer

FOXM1 represents a potential therapeutic target in the fight against cancer as it is seen to be upregulated in numerous human malignancies, but it is not expressed in non-dividing normal cells, thus promising specificity toward cancer cells in a targeted approach. FOXM1 is involved in so many aspects of tumorigenesis including proliferation, invasion, migration, angiogenesis, metastasis, resistance to apoptosis among others. Consequently, targeting FOXM1 could have diverse effects and could disrupt the development and progression of cancer at multiple levels. Some cells can tolerate the absence of FOXM1 and retain the ability to grow and form tumors suggesting that there are mechanisms that can compensate for the loss of this protein. As suppression of FOXM1 is gaining more clinical relevance, the discovery of the mechanisms of resistance to anti-FOXM1 treatment clearly gains importance. Whether resistance is achieved via gain- or loss-of-function changes, there are now well-established functional genetic techniques to discover such events. In addition, interactions of FOXM1 with other proteins could offer efficient targeting options, since targeting one partner would affect the other and their downstream targets. The summarized findings support that targeting FOXM1 alone or in combination could be an effective therapeutic strategy against human malignancies.

References:

Raychaudhuri P, et al. FoxM1: A Master Regulator of Tumor Metastasis. Cancer Research, 2011, 71(13):4329-33.
Koo C Y, et al. FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta, 2012, 1819(1):0-37.
Halasi M, Gartel A L. Targeting FOXM1 in cancer. Biochemical Pharmacology, 2013, 85(5):644-652.
Bella L, et al. FOXM1: A key oncofoetal transcription factor in health and disease. Seminars in Cancer Biology, 2014, 29:32-39.

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