FOXM1: A key oncofoetal transcription factor in health and disease

Bella, Laura; Zona, Stefania; Moraes, Gabriela Nestal de; Lam, Eric W.‐F.

doi:10.1016/j.semcancer.2014.07.008

Cited by 133 publications

(114 citation statements)

References 73 publications

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“…Such promoter-specific activity of FoxM1 may be caused by how Brg1 rearranges the chromatin-DNA for FoxM1 to bind or by other unidentified factors in the promoter that differentially expose or enable the FoxM1 transactivating or repressor domain. Given that FoxM1 is required for embryogenesis and is a protooncogene up-regulated in many human cancers, including lung, breast, and colon cancers (25)(26)(27)47), future studies to define the molecular details of the differential domain use of FoxM1 may have important implications in organ development, cardiac hypertrophy, and many other diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Given the lack of ACE2 drugs that limit full clinical exploitation of this pathway, targeting the Brg1-FoxM1 complex may offer an alternative strategy for concurrent ACE and ACE2 control in heart failure therapy. Furthermore, the studies demonstrated a molecular interaction between Brg1 and FoxM1 in gene control, which provides novel insights into the mechanisms of FoxM1-mediated organ development and oncogenic processes (25)(26)(27).…”

Section: Significancementioning

confidence: 99%

“…First, FoxM1 regulates the expression of genes associated with pathological hypertrophy (37,38). Second, the FoxM1 protein contains both transactivation and repressor domains, capable of functioning as a transcription activator or repressor (25)(26)(27). Third, we found that FoxM1 had expression dynamics in fetal, normal adult, and stressed adult hearts, similar to that of Brg1.…”

Section: Endothelial Foxm1 Is Required For Stress-induced Cardiac Hypmentioning

confidence: 99%

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Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Yang

Feng

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Endothelial Foxm1 Is Required For Stress-induced Cardiac Hypmentioning

confidence: 99%

See 1 more Smart Citation

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Yang

Feng

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This is due to the ability of insulin to activate PI3K-AKT signalling, which can in turn induce anti-apoptosis and chemoresistance in tumour cells (Ungefroren et al, 2015). FOXO3 and FOXM1 have antagonistic functions in the regulation of their target genes and this axis can modulate chemotherapy resistance (Zhao and Lam, 2012;Bella et al, 2014). FOXM1 has also been demonstrated to play a crucial role in cancer chemotherapeutic drug resistance Lam, 2007, 2008;Zona et al, 2014;Zhao and Lam, 2012;Bella et al, 2014;Chen et al, 2010).…”

Section: Insulin Signallingmentioning

confidence: 99%

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

Saavedra‐García

Nichols

Mahmud

et al. 2018

Molecular and Cellular Endocrinology

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Keywords:Fatty acids Cancer Lipid metabolism FOXO3 FOXM1 AKT/PI3K pathway a b s t r a c t Obesity and cachexia represent divergent states of nutritional and metabolic imbalance but both are intimately linked to cancer. There is an extensive overlap in their signalling pathways and molecular components involved such as fatty acids (FAs), which likely play a crucial role in cancer. Forkhead box (FOX) proteins are responsible of a wide range of transcriptional programmes during normal development, and the FOXO3-FOXM1 axis is associated with cancer initiation, progression and drug resistance.Free fatty acids (FFAs), FA synthesis and b-oxidation are associated with cancer development and progression. Meanwhile, insulin and some adipokines, that are up-regulated by FAs, are also involved in cancer development and poor prognosis. In this review, we discuss the role of FA metabolism in cancer and how FA metabolism integrates with the FOXO3-FOXM1 axis. These new insights may provide leads to better cancer diagnostics as well as strategies for tackling cancer development, progression and drug resistance.

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“…Recent experimental studies have suggested that activation of FOXM1 and its downstream target genes contribute to aggressive tumor growth, angiogenesis and invasion, resulting in tumor progression [3]. Furthermore, combined analysis of FOXM1 and its targets also showed prognostic implication in clinical cancer samples [4,5].…”

mentioning

confidence: 99%

Expression of CDCA8 correlates closely with FOXM1 in breast cancer: public microarray data analysis and immunohistochemical study

Jiao¹,

Lu²,

Qiao³

et al. 2015

neo

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Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in breast cancer progression and metastasis. However, the clinical significance of FOXM1 and its associated signaling genes in human breast cancer still needed to be clarified. In this study, we first analyzed the co-expression gene pattern of FOXM1 in three breast cancer gene expression microarray datasets from the Oncomine database. Cell division cycle associated 8 (CDCA8) gene was identified to correlate closely with FOXM1. In silico analysis further indicated that CDCA8 overexpressed in breast cancer tissues compared with the normal controls is significantly associated with the triple-negative phenotype. Experimentally, we performed a immunohistochemical study to detect the expression of CDCA8 in 112 breast cancer samples, and evaluated its clinicopathological and prognostic significance. We found that CDCA8 was frequently over-expressed in breast cancer tissues, and increased expression of CDCA8 was positively associated with FOXM1 expression, triple-negative phenotype and shorter overall survival. Moreover, we also found that combination of CDCA8 and FOXM1 showed a higher hazard ratio than the individual markers. Our results suggest that FOXM1-CDCA8 signature might be involved in breast cancer progression, and serves as a potential prognostic factor and a promising therapeutical target.

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FOXM1: A key oncofoetal transcription factor in health and disease

Cited by 133 publications

References 73 publications

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

Expression of CDCA8 correlates closely with FOXM1 in breast cancer: public microarray data analysis and immunohistochemical study

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