Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

Zhang, Lei; Cai, Meizhen; Gong, Zhicheng; Zhang, Bingchang; Li, Yuanpei; Guan, Li; Hou, Xiaonan; Li, Qing; Liu, Gang; Xue, Zhe; Yang, Muh Hua; Ye, Jing; Chin, Y. Eugene; You, Han

doi:10.1172/jci90077

Cited by 49 publications

(58 citation statements)

References 53 publications

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“…Two major proteins in the FoxO family are FoxO1 and FoxO3. Although the DNA-binding domains (DBDs) of FoxO1 and FoxO3 are highly homologous, sequence conservation outside of the DBD is low (28). It is known that FoxO1 and FoxO3 have both overlapping and distinctive functions (29).…”

Section: Resultsmentioning

confidence: 99%

ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation

Shin

Buel

Nagiec

et al. 2019

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

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ERK is a key coordinator of the epithelial-to-mesenchymal transition (EMT) in that a variety of EMT-inducing factors activate signaling pathways that converge on ERK to regulate EMT transcription programs. However, the mechanisms by which ERK controls the EMT program are not well understood. Through an analysis of the global changes of gene expression mediated by ERK2, we identified the transcription factor FoxO1 as a potential mediator of ERK2induced EMT, and thus we investigated the mechanism by which ERK2 regulates FoxO1. Additionally, our analysis revealed that ERK2 induced the expression of Dock10, a Rac1/Cdc42 GEF, during EMT. We demonstrate that the activation of the Rac1/JNK signaling axis downstream of Dock10 leads to an increase in FoxO1 expression and EMT. Taken together, our study uncovers mechanisms by which epithelial cells acquire less proliferative but more migratory mesenchymal properties and reveals potential therapeutic targets for cancers evolving into a metastatic disease state. ERK2 | epithelial-to-mesenchymal transition | EMT | FoxO | Dock10

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Section: Resultsmentioning

confidence: 99%

ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation

Shin

Buel

Nagiec

et al. 2019

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

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“…While being essential for the maintenance of genome stability, we have previously shown that geminin acts as a tumor suppressor in the murine colon and lung cancer model (4). In addition, it is frequently overexpressed in several human cancers and a recent study has shown that geminin overexpression promotes breast cancer metastasis through FoxO3 deacetylation (88). Geminin is, therefore, involved in cancer, development and pluripotency.…”

Section: Resultsmentioning

confidence: 99%

DNA Replication Inhibitor Geminin and Retinoic Acid Signaling Participate in Complex Interactions Associated With Pluripotency

Tsaniras

Petropoulos

Παναγόπουλος

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Several links between DNA replication, pluripotency and development have been recently identified. The involvement of miRNA in the regulation of cell cycle events and pluripotency factors has also gained attention. Materials and Methods: In the present study, we used the g:Profiler platform to analyze transcription factor binding sites, miRNA networks and protein-protein interactions to identify novel links among the aforementioned processes. Results and Conclusion: A complex circuitry between retinoic acid signaling, SWI/SNF components, pluripotency factors including Oct4, Sox2 and Nanog and cell cycle regulators was identified. It is suggested that the DNA replication inhibitor geminin plays a central role in this circuitry.

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“…FOXO3 is a transcription factor belonging to the O subclass of the forkhead family. It is thought to be associated with tumorigenesis, immunoregulation, and even longevity of humans [41][42][43][44][45] . Besides, researchers discovered that FOXO3 regulates neurogenesis in adult by interacting with ten-eleven translocation-2 protein 46 and maintains redox balance in neural stem cells coordinating metabolic pathways 47 .…”

Section: Discussionmentioning

confidence: 99%

Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation

Deng¹,

Li²,

Zhang³

et al. 2020

Cell Death Dis

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Nowadays, immune diseases are a large burden in healthcare. Mesenchymal stem cells (MSCs) have prominent ability in immunomodulation and have been applicated on treating many immune-related diseases. However, the clinical outcomes can be disparate and sometimes completely counterproductive beyond explanation of cell heterogeneity. The theory of immunomodulation plasticity in MSCs has then emerged to explain that MSCs can be induced into proinflammatory MSC1 or anti-inflammatory MSC2 responding to different immune environment. It would be safer and more efficient if we could induce MSCs into a certain immune phenotype, in most cases MSC2, prior to medical treatment. In this study, we screened and identified a classical FDA-approved drug, chlorzoxazone (CZ). Unlike traditional method induced by IFN-γ, CZ can induce MSC into MSC2 phenotype and enhance the immunosuppressive capacity without elevation of immunogenicity of MSCs. CZ-treated MSCs can better inhibit T cells activation and proliferation, promote expression of IDO and other immune mediators in vitro, and alleviate inflammatory infiltration and tissue damage in acute kidney injury rat model more effectively. Moreover, we discovered that CZ modulates phosphorylation of transcriptional factor forkhead box O3 (FOXO3) independent of classical AKT or ERK signaling pathways, to promote expression of downstream immune-related genes, therefore contributing to augmentation of MSCs immunosuppressive capacity. Our study established a novel and effective approach to induce MSC2, which is ready for clinical application.

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Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

Cited by 49 publications

References 53 publications

ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation

ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation

DNA Replication Inhibitor Geminin and Retinoic Acid Signaling Participate in Complex Interactions Associated With Pluripotency

Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation

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