Multiple faces of FoxM1 transcription factor

Kalin, Tanya V.; Ustiyan, Vladimir; Kalinichenko, Vladimir V.

doi:10.4161/cc.10.3.14709

Cited by 180 publications

(148 citation statements)

References 76 publications

(130 reference statements)

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“…Our in vitro and in vivo studies demonstrated that SPDEF inhibits Cdc25b , Cyclin B1 , Cyclin A2 , Plk1 , Cks1 , Aurora B , and Topo 2 alpha mRNAs, all of which are known targets of Foxm1 transcription factor [29]. Since Foxm1 is up-regulated in mouse and human prostate cancers and is required for prostate carcinogenesis [8], [10], we tested whether SPDEF inhibits Foxm1.…”

Section: Resultsmentioning

confidence: 99%

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

et al. 2014

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SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the −745/−660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo.

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Section: Resultsmentioning

confidence: 99%

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

et al. 2014

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“…It is a key cell-cycle regulator of both the transition from G1 to S phase and the progression to mitosis [14][15][16]. It has been shown to play important roles in regulating the expression of genes involved in cell proliferation, differentiation, and transformation [17]. Increased expression of FoxM1 has been found in several human tumors suggesting a role in human carcinogenesis [13,[18][19][20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients

Wang

Zhao

et al. 2013

Lung Cancer

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“…In adult organs, FOXM1 is mainly expressed in proliferating cells or induced by growth factor release. In this context, it is not surprising that FOXM1 serves as proto-oncogene in most cancers and aberrant expression or mutations constitute the origin of many treatment resistance mechanisms (Kwok et al 2010; Kalin et al 2011; Saba et al 2016). Although FOXM1 is exclusively expressed in dividing cells, its targeting may result in many side effects given its involvement in angiogenesis, cell migration and epithelial–mesenchymal transition (Halasi and Gartel 2013).…”

Section: Introductionmentioning

confidence: 99%

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

Rinaldetti

Wirtz²,

Worst

et al. 2018

J Cancer Res Clin Oncol

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PurposeThe proto-oncogene forkhead box M1 (FOXM1) is associated with poor survival in many cancers. The impact of FOXM1 expression on progression-free survival (PFS) of non-muscle invasive bladder cancer (NMIBC) has not yet been investigated. The differential expression of FOXM1 between the different molecular NMIBC subtypes has further been assessed.MethodsTranscript levels of FOXM1 and MKI67 were determined in 460 NMIBC patients (UROMOL cohort) by RNA-Seq and validated in silico by the Chungbuk and Lund cohort (n = 277). FOXM1 and MKI67 cutoffs were identified by the minimal p value method. Variables were evaluated by multivariable Cox regression analyses in order to identify independent predictors.ResultsFOXM1 is an independent predictor for PFS superior to current histological, clinical and molecular staging methods. Patients with high FOXM1 expression have a 6- to 8-fold higher risk of progression in multivariable analysis (p < 0.03). Highest transcript levels were found in the Class 2 and genomically unstable molecular NMIBC subtype (p < 0.03). The proto-oncogene further positively correlated with tumor grade and stage. NMIBCs with high FOXM1 expression showed a PFS advantage when treated with intravesical BCG instillation.ConclusionFOXM1 is a highly prognostic marker for disease progression of NMIBC superior to current histological, clinical and molecular staging methods and MKI67. It is mainly expressed in the Class 2 and genomically unstable molecular bladder cancer subtypes. Its role in drug resistance development makes FOXM1 valuable biomarker for NMIBC risk stratification.

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Multiple faces of FoxM1 transcription factor

Cited by 180 publications

References 76 publications

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

FoxM1 expression is significantly associated with cisplatin-based chemotherapy resistance and poor prognosis in advanced non-small cell lung cancer patients

FOXM1 predicts disease progression in non-muscle invasive bladder cancer

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