FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation

Yang, Fei; Xu, Jie; Li, Hua; Tan, Mingjia; Xiong, Xiufang; Sun, Yi

doi:10.1038/s41467-019-09289-5

Cited by 75 publications

(64 citation statements)

References 56 publications

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“…2A). We have recently defined the consensus-binding motif (TSXXXS) required for FBXW2 to bind to its substrates, such as SKP2 (22) and β-catenin (23). Examination of the MSX2 protein sequence indeed identified such a motif, which is evolutionarily conserved ( 43 SSLPFS 48 ) (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

Yin

Xie

et al. 2019

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

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SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2–FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2–MSX2–SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.

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Section: Resultsmentioning

confidence: 99%

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

Yin

Xie

et al. 2019

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

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“…FBXW2 (F-box and WD repeat domain containing 2) plays a role in the regulation of protein polyubiquitination, cellular protein modification process, proteolysis. Yang found that FBXW2 can participate in the occurrence and development of lung cancer by regulating epidermal growth factor-AKT1, β -catenin [ 44 ]. There are few reports related to FBXW2 involving in pain regulation.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Genes and Mechanisms in Postherpetic Neuralgia

Qiu

Hao

Cheng

et al. 2020

Pain Research and Management

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Objective. Elderly patients are prone to postherpetic neuralgia (PHN), which may cause anxiety, depression, and sleep disorders and reduce quality of life. As a result, the life quality of patients was seriously reduced. However, the pathogenesis of PHN has not been fully elucidated, and current treatments remain inadequate. Therefore, it is important to explore the molecular mechanism of PHN. Methods. We analyzed the GSE64345 dataset, which includes gene expression from the ipsilateral dorsal root ganglia (DRG) of PHN model rats. Differentially expressed genes (DEGs) were identified and analyzed by Gene Ontology. Protein-protein interaction (PPI) network was constructed. The miRNA associated with neuropathic pain and inflammation was found in miRNet. Hub genes were identified and analyzed in Comparative Toxicogenomics Database (CTD). miRNA-mRNA networks associated with PHN were constructed. Results. A total of 116 genes were up-regulated in the DRG of PHN rats, and 135 genes were down-regulated. Functional analysis revealed that variations were predominantly enriched for genes involved in neuroactive ligand-receptor interactions, the Jak-STAT signaling pathway, and calcium channel activity. Eleven and thirty-one miRNAs associated with neuropathic pain and inflammation, respectively, were found. Eight hub genes (S1PR1, OPRM1, PDYN, CXCL3, S1PR5, TBX5, TNNI3, MYL7, PTGDR2, and FBXW2) associated with PHN were identified. Conclusions. Bioinformatics analysis is a useful tool to explore the mechanism and pathogenesis of PHN. The identified hub genes may participate in the onset and development of PHN and serve as therapeutic targets.

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“…For instance, β-catenin can directly activate the transcription of E-box repressors Snail, Slug, and Twist to promote epithelial-mesenchymal transition and facilitate metastasis (Yang et al, 2013). In addition, β-catenin enhances the mobility of metastasizing cancer cells by activating the transcription of a panel of different metalloproteinases (MMPs) to contribute to the remodeling of the extracellular matrix (Lowy et al, 2006;Kamino et al, 2011;Yang F. et al, 2019). Regulation of MMPs by several mechanisms including transcriptional activation via promoter and via miRNAs plays important roles in the remodeling of extracellular matrix (Surgucheva et al, 2003;Surgucheva et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

Sun

Chen

et al. 2020

Front. Cell Dev. Biol.

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A disintegrin and metalloproteinase (ADAM) family of proteins play versatile roles in cancer development and progression. In the present study, we investigated the role of ADAM proteins in colorectal cancer (CRC) cell migration and invasion focusing on the epigenetic mechanism whereby ADAM transcription is regulated. We report that higher levels of ADAM10, ADAM17, and ADAM19 were detected in SW480 cells than in HCT116 cells. Expression levels of the same set of ADAMs were higher in human CRC biopsy specimens of advanced stages than in those of a less aggressive phenotype. Overexpression of ADAM10/17/19 in HCT116 cells enhanced, whereas depletion of ADAM10/17/19 in SW480 cells weakened, migration and invasion. ADAM expression was activated by the Wnt signaling pathway, which could be attributed to direct binding of β-catenin on the ADAM promoters. Mechanistically, β-catenin recruited the chromatin remodeling protein BRG1, which in turn enlisted histone demethylase KDM4 to alter the chromatin structure, thereby leading to ADAM transactivation. In conclusion, our data suggest that the Wnt signaling may promote CRC metastasis, at least in part, by recruiting an epigenetic complex to activate ADAM transcription.

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FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation

Cited by 75 publications

References 56 publications

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

Bioinformatics Analysis of Genes and Mechanisms in Postherpetic Neuralgia

Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

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