FOXM1 in Cancer: Interactions and Vulnerabilities

Gartel, Andrei L.

doi:10.1158/0008-5472.can-16-3566

Cited by 181 publications

(153 citation statements)

References 30 publications

(62 reference statements)

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“…Well-differentiated epithelial-like cells have high CNI, whereas low CNI cells have abnormally-shaped nuclei ( Figure 1D). Consistent with the idea that low CNI is a marker of cancer progression and aggressiveness, this score was strongly and negatively associated with the mRNA levels of genes previously implicated in breast tumorigenesis including MCM4 35 , MCM10 36 , FOXM1 37 , CCNE2 38 , and MASTL 39 (Figure 1B). In addition, besides median I1 as an average measure, heterogeneity measures including standard deviation and skewness of morphology scores were also identified in this core network module;…”

Section: Hybrid Network Topological Analysis Revealed Tumour Morpholosupporting

confidence: 83%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

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Section: Hybrid Network Topological Analysis Revealed Tumour Morpholosupporting

confidence: 83%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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“…In addition, FOXM1 expression is a major predictor of poor outcome across a large set of cancer types [7]. This strongly supports the concept of FOXM1 as an actionable target for therapy [3,6] and encourages further exploration of FOXM1 function.…”

Section: Introductionsupporting

confidence: 59%

“…These proteins also play a pivotal role in the progression of cancers. The most important Forkhead Box (FOX) transcription factor involved in a multitude of pro-tumorigenic processes is FOXM1 [2,3]. The main gene regulatory activity of FOXM1 is attributed to cell cycle and mitotic control [4,5].…”

Section: Introductionmentioning

confidence: 99%

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The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

Roh

Hiou‐Feige

Misetic

et al. 2019

The Journal of Pathology

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Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three-dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated-like phenotype, indicating a context-dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC.No conflicts of interest were declared. heterogeneous expression of keratins [10][11][12].Despite a large body of evidence that FOXM1 has a role in HNSCC [13][14][15][16], its oncogenic functions in this type of cancer are not yet sufficiently understood. In Figure 3. shRNA-mediated FOXM1 knockdown decreases the number of proliferating cells and facilitates progression towards a more differentiated-like phenotype. (A) H&E staining of CAL27 organotypic cultures demonstrating a squamous-like phenotype after 16 days of culture. Scale bar = 100 μm. (B) Representative pictures of immunostaining for a series of indicated differentiation markers in CAL27 organotypic cultures at day 16. Scale bar = 100 μm. (C) RT-qPCR analysis of organotypes showing a gradual decrease in FOXM1 and its targets CCNF and GTSE1 upon FOXM1 knockdown, while differentiation-related genes such as JUND and IVL were upregulated both by FOXM1 knockdown and by increased time of culture. The data shown are from one experiment. (D) RT-qPCR analysis of FOXM1 and IVL expression levels in a large series of CAL27 shCtr or shFOXM1 organotypic cultures showing a trend for IVL upregulation following FOXM1 knockdown. Each dot represents one organotype. (E) FOXM1 expression was reduced by culturing cells in 3D organotypes as demonstrated by the reduction of FOXM1 transcript level measured by RT-qPCR. Each data point represents one sample under one condition or the other. (F) Computer-assisted quantification of the number of Ki-67-positive cells detected by immunohistochemistry in shCtr and FOXM1-depleted organotypes. Each data point represents one analyzed field of the organotype. (G) Examples for the Ki-67 immunohistochemistry data quantified in panel F. Ki-67-positive cells were detected in the basal layer for both conditions at day 8. In the control, cycling cells were present throughout the organotype at day 16, while they were restricted to the basal layer upon FOXM1 downregu...

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“…6 Many studies found that FoxM1 is a member of the Fox transcription factor family. 6 Many studies found that FoxM1 is a member of the Fox transcription factor family.…”

Section: Introductionmentioning

confidence: 99%

MiR‐216b inhibits osteosarcoma cell proliferation, migration, and invasion by targeting Forkhead Box M1

Wang

Guo

et al. 2018

J of Cellular Biochemistry

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Osteosarcoma (OS) is considered the most common type of primary malignant bone tumor, which has a high rate of mortality in children and adolescents. However, the current treatment methods for OS are ineffective. Therefore, there is an urgent requirement to identify the critical targets. This study aimed to identify the roles and significance of microRNA‐216b (miR‐216b) in OS. To explore the cellular and molecular functions of miR‐216b and Forkhead Box M1 (FoxM1) in OS, the expression of miR‐216b and FoxM1 at the transcriptional level was measured using quantitative real‐time PCR (qRT‐PCR). Wound healing assay, 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyltetrazolium bromide assay (MTT) assay, flow cytometry, and transwell invasion assay were conducted to study the function of miR‐216b and FoxM1 in OS cells. Dual luciferase reporter assay was performed to identify the relationships between miR‐216b and FoxM1. qRT‐PCR results revealed that miR‐216b expression was significantly downregulated, and FoxM1 was observed to be significantly upregulated in human OS cell lines (MG‐63) and tissues. MTT data showed that upregulation of miR‐216b expression led to cell growth inhibition in MG‐63 cells. The results of the invasion assay and wound healing assay illustrated that miR‐216b upregulation or FoxM1 downregulation could inhibit the invasion and migration in MG‐63 cells. In vivo, the tumor volume was significantly decreased by miR‐194 mimic treatment compared with the control group. Furthermore, the results of the luciferase assay indicated that FoxM1 is a direct target of miR‐216b. These findings may provide novel insights into the molecular mechanism of miR‐216b and FoxM1 in the progression of OS, and suggested that miR‐216b may serve as a potential tumor inhibitor of OS by targeting FoxM1.

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FOXM1 in Cancer: Interactions and Vulnerabilities

Cited by 181 publications

References 30 publications

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

MiR‐216b inhibits osteosarcoma cell proliferation, migration, and invasion by targeting Forkhead Box M1

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