The Rho GTPase RhoB regulates cadherin expression and epithelial cell-cell interaction

Vega, Francisco; Thomas, Mairian; Reymond, Nicolas; Ridley, Anne J.

doi:10.1186/s12964-015-0085-y

Cited by 27 publications

(24 citation statements)

References 32 publications

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“…In parallel, E-cadherin, epithelial marker of EMT known to be downregulated notably by Slug, showed reduced levels of mRNA and protein. Similarly, it was reported very recently in prostate cancer cells 41 that RhoB silencing reduced E-cadherin expression only at the protein level, thus by a protein degradation rather than by a transcriptional regulatory mechanism. Interestingly, Slug expression is associated with poor survival in lung carcinoma, 42 similar to the loss of RhoB expression.…”

Section: Discussionsupporting

confidence: 69%

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

et al. 2015

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Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which is mainly due to its high risk of metastatic dissemination. One critical point of this process is the ability of cancer cells to detach from the primary tumor and migrate through the extracellular matrix; however, the underlying molecular mechanisms are not yet fully understood. In the present study, we identified the small GTPase RhoB as a key regulator of bronchial cell morphology in a three-dimensional (3D) matrix. RhoB loss, which is frequently observed during lung cancer progression, induced an epithelial-mesenchymal transition (EMT) characterized by an increased proportion of invasive elongated cells in 3D. The process was mediated by Slug induction and E-cadherin repression. In addition, downregulation of RhoB induced Akt1 activation, which in turn activated Rac1 through the guanine-exchange factor Trio to control cell shape rearrangement. Further, we provide evidence that RhoB interacted with and positively regulates phosphatase PP2A through the recruitment of its regulatory subunit B55, which was found to be crucial for Akt dephosphorylation. B55 inhibition completely suppressed RhoB-mediated PP2A regulation. Finally, we show that PP2A inactivation, by targeting either its catalytic or its regulatory B55 subunit, completely reversed RhoB-dependent morphological changes and also fully prevented the ability of RhoB to decrease the invasiveness of bronchial cells. Altogether, these results highlight a novel signaling axis and describe new molecular mechanisms that could explain the tumor suppressor role of RhoB in lung cancer. Therefore, we propose that RhoB could be responsible for early metastatic prevention by inhibiting the EMT-derived invasiveness of lung cells through the control of PP2A activity.

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Section: Discussionsupporting

confidence: 69%

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

et al. 2015

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“…Rho signaling governs actin redistribution [32-41] and is implicated in various cellular responses including cell-cell adhesion and EMT [13, 22, 25, 42-45]. In the present work, we reported opposite effects of the KDM2B gene in the expression of RhoA/RhoB/RhoC- and Rac1-GTPases.…”

Section: Discussionsupporting

confidence: 56%

“…This observation implies a significant role of KDM2B in tumorigenesis and suggests the implication of actin cytoskeleton and small GTPases signaling in this phenomenon. Indeed, this assumption was postulated previously in various tumor cell models by analyzing the correlation of EMT with actin signaling and migration [13, 19-27]. Moreover, previous studies showed that the Serum glucocorticoid kinase 1 (Sgk1) plays a key role in EMT in colon carcinoma [28].…”

Section: Discussionmentioning

confidence: 84%

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

Zacharopoulou

Tsapara

Kallergi

et al. 2018

Cell Physiol Biochem

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Background/Aims: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. Methods: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins. Results: We report here that KDM2B regulates EZH2 and BMI1 in HCT116 colon tumor cells. Knockdown of this epigenetic factor induced potent up-regulation of the protein levels of the epithelial markers E-cadherin and ZO-1, while the mesenchymal marker N-cadherin was downregulated. On the other hand, KDM2B overexpression downregulated the levels of both epithelial markers and upregulated the mesenchymal marker, suggesting control of EMT by KDM2B. In addition, RhoA, RhoB and RhoC protein levels diminished upon KDM2B-knockdown, while all three small GTPases became upregulated in KDM2B-overexpressing HCT116 cell clones. Interestingly, Rac1 GTPase level increased upon KDM2B-knockdown and diminished in KDM2B-overexpressing HCT116 colon tumor- and DU-145 prostate cancer cells. Conclusions: These results establish a clear functional role of the epigenetic factor KDM2B in the regulation of EMT and small-GTPases expression in colon tumor cells and further support the recently postulated oncogenic role of this histone demethylase in various tumors.

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“…However, recent data have shown that RhoB expression is induced under conditions such as DNA damage, or treatment with growth factors or cytokines, suggesting that under particular circumstances, RhoB may favor towards human malignancy, including glioblastoma tumors [65,66]. In the present study, we show that when RhoB is silenced, both parental and their derivative-IE1 cells show a reduction in spread area compared to the RhoA or RhoC knockdown cells, an effect which has attributed to subsequent reduction of total surface levels of b1 integrin [67,68]. Moreover, in the presence of HCMV, an increased number of cellular projections was formed, a phenomenon which has also been observed in HCMV infected primary HFF cells, particularly at the late stages of lytic infection [49].…”

Section: Discussionsupporting

confidence: 53%

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

Tseliou

Al‐Qahtani²,

Alarifi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. Methods: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. Results: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. Conclusion: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state.

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The Rho GTPase RhoB regulates cadherin expression and epithelial cell-cell interaction

Cited by 27 publications

References 32 publications

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition

The Epigenetic Factor KDM2B Regulates EMT and Small GTPases in Colon Tumor Cells

The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells

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