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FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer.

ABSTRACT: FoxM1 activates genes that regulate S-G2-M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of non-perpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2-RhoAmDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 GEF activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

SUBMITTER: Limzerwala JF

PROVIDER: S-EPMC8623810 | biostudies-literature |

REPOSITORIES: biostudies-literature

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FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer

Project description:FoxM1 activates genes that regulate S-G2-M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of non-perpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2-RhoA-mDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 GEF activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

2020-07-09 | GSE130410 | GEO

FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer

Project description:FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer

| PRJNA540152 | ENA

Annexin V-induced rat Leydig cell proliferation involves Ect2 via RhoA/ROCK signaling pathway.

Project description:This study investigated the effect of annexin V on the proliferation of primary rat Leydig cells and the potential mechanism. Our results showed that annexin V promoted rat Leydig cell proliferation and cell cycle progression in a dose- and time-dependent manner. Increased level of annexin V also enhanced Ect2 protein expression. However, siRNA knockdown of Ect2 attenuated annexin V-induced proliferation of rat Leydig cells. Taken together, these data suggest that increased level of annexin V induced rat Leydig cell proliferation and cell cycle progression via Ect2. Since RhoA activity was increased following Ect2 activation, we further investigated whether Ect2 was involved in annexin V-induced proliferation via the RhoA/ROCK pathway, and the results showed that annexin V increased RhoA activity too, and this effect was abolished by the knockdown of Ect2. Moreover, inhibition of the RhoA/ROCK pathway by a ROCK inhibitor, Y27632, also attenuated annexin V-induced proliferation and cell cycle progression. We thus conclude that Ect2 is involved in annexin V-induced rat Leydig cell proliferation through the RhoA/ROCK pathway.

| S-EPMC5380157 | biostudies-literature

RHOA and mDia1 Promotes Apoptosis of Breast Cancer Cells Via a High Dose of Doxorubicin Treatment.

Project description:BackgroundTransforming RhoA proteins (RHOA) and their downstream Diaphanous homolog 1 proteins (DIAPH1) or mDia1 participate in the regulation of actin cytoskeleton which plays critical role in cells, i.e., morphologic changes and apoptosis.MethodologyTo determine the cell viability the real time cell analysis (RTCA) and flow cytometry were used. To perform proteomic analysis, the label-free quantitative method and post-translation modification by the nano-HPLC and ESI-MS ion trap mass analyser were used.ResultsThe results of the cell viability showed an increase of dead cells (around 30 %) in MCF-7/DOX-1 (i.e., 1μM of doxorubicin was added to MCF-7/WT breast cancer cell line) compared to MCF-7/WT (control) after 24 h doxorubicin (DOX) treatment. The signalling pathway of the Regulation of actin cytoskeleton (p<0.0026) was determined, where RHOA and mDia1 proteins were up-regulated. Also, post-translational modification analysis of these proteins in MCF-7/DOX-1 cells revealed dysregulation of the actin cytoskeleton, specifically the collapse of actin stress fibbers due to phosphorylation of RHOA at serine 188 and mDia1 at serine 22, resulting in their deactivation and cell apoptosis.ConclusionThese results pointed to an assumed role of DOX to dysregulation of actin cytoskeleton and cell death.

| S-EPMC7874778 | biostudies-literature

Cytokinetic diversity in mammalian cells is revealed by the characterization of endogenous anillin, Ect2 and RhoA.

Project description:Cytokinesis is required to physically separate the daughter cells at the end of mitosis. This crucial process requires the assembly and ingression of an actomyosin ring, which must occur with high fidelity to avoid aneuploidy and cell fate changes. Most of our knowledge of mammalian cytokinesis was generated using over-expressed transgenes in HeLa cells. Over-expression can introduce artefacts, while HeLa are cancerous human cells that have lost their epithelial identity, and the mechanisms controlling cytokinesis in these cells could be vastly different from other cell types. Here, we tagged endogenous anillin, Ect2 and RhoA with mNeonGreen and characterized their localization during cytokinesis for the first time in live human cells. Comparing anillin localization in multiple cell types revealed cytokinetic diversity with differences in the duration and symmetry of ring closure, and the timing of cortical recruitment. Our findings show that the breadth of anillin correlates with the rate of ring closure, and support models where cell size or ploidy affects the cortical organization, and intrinsic mechanisms control the symmetry of ring closure. This work highlights the need to study cytokinesis in more diverse cell types, which will be facilitated by the reagents generated for this study.

| S-EPMC9683116 | biostudies-literature

RHOA inactivation enhances Wnt signaling and promotes colorectal cancer

Project description:Microarray transcriptomic analysis of formalin-fixed, paraffin-embedded small intestinal tumors from control (Apcmin/+;Vil-Cre-/-;RhoADN/-) and DN-RhoA (Apcmin/+;Vil-CreTG/-;RhoADN/-) mice.

2014-11-21 | E-MTAB-2981 | biostudies-arrayexpress

Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration.

Project description:In animals, cells often move as collectives to shape organs, close wounds, or-in the case of disease-metastasize. To accomplish this, cells need to generate force to propel themselves forward. The motility of singly migrating cells is driven largely by an interplay between Rho GTPase signaling and the actin network (Yamada and Sixt, 2019). Whether cells migrating as collectives use the same machinery for motility is unclear. Using the zebrafish posterior lateral line primordium as a model for collective cell migration, we find that active RhoA and myosin II cluster on the basal sides of the primordium cells and are required for primordium motility. Positive and negative feedbacks cause RhoA and myosin II activities to pulse. These pulses of RhoA signaling stimulate actin polymerization at the tip of the protrusions and myosin II-dependent actin flow and protrusion retraction at the base of the protrusions, and deform the basement membrane underneath the migrating primordium. This suggests that RhoA-induced actin flow on the basal sides of the cells constitutes the motor that pulls the primordium forward, a scenario that likely underlies collective migration in other-but not all (Bastock and Strutt, 2007; Lebreton and Casanova, 2013; Matthews et al., 2008)-contexts.

| S-EPMC10592895 | biostudies-literature

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK.

Project description:The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-?N3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that process.

| S-EPMC4682630 | biostudies-literature

Long non‑coding RNA 01614 hyperactivates WNT/β‑catenin signaling to promote pancreatic cancer progression by suppressing GSK‑3β.

Project description:Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC‑related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease‑free survival of patients with PC according to the analysis of The Cancer Genome Atlas‑derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion in vitro, and inhibited tumor proliferation in vitro and in vivo. Mechanistically, linc01614 overexpression stabilized the level of β‑catenin protein to hyperactivate the WNT/β‑catenin signaling pathway in PC cells. Further analyses revealed that linc01614 bound to GSK‑3β and perturbed the interaction between GSK‑3β and AXIN1, thereby preventing the formation of the β‑catenin degradation complex and reducing the degradation of β‑catenin. In summary, the present findings reveal that linc01614 may function as an oncogene and promote the progression of PC and may thus be considered as a potential therapeutic target in the future.

| S-EPMC9387559 | biostudies-literature

A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis.

Project description:Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its precise functional roles and regulation remain unclear. In this study, we determined the oncogenic function of Cav-1 in preclinical models of pancreatic cancer and in human tissue specimens. Cav-1 expression levels correlated with metastatic potential and epithelial-mesenchymal transition (EMT) in both mouse and human pancreatic cancer cells. Elevated levels in cells promoted EMT, migration, invasion, and metastasis in animal models, whereas RNA interference (RNAi)-mediated knockdown inhibited these processes. We determined that levels of Cav-1 and the Forkhead transcription factor FoxM1 correlated directly in pancreatic cancer cells and tumor tissues. Enforced expression of FoxM1 increased Cav-1 levels, whereas RNAi-mediated knockdown of FoxM1 had the opposite effect. FoxM1 directly bound to the promoter region of Cav-1 gene and positively transactivated its activity. Collectively, our findings defined Cav-1 as an important downstream oncogenic target of FoxM1, suggesting that dysregulated signaling of this novel FoxM1-Cav-1 pathway promotes pancreatic cancer development and progression.

| S-EPMC3271134 | biostudies-literature

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