FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein

Zhang, Yong; Zhang, Xinxin; Ye, Mingxiang; Jing, Pengyu; Xiong, Jie; Han, Zhiping; Kong, Jing; Li, Mengyang; Lai, Xiaofeng; Chang, Ning; Zhang, Jian

doi:10.1016/j.canlet.2018.01.047

Cited by 49 publications

(41 citation statements)

References 28 publications

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“…Snail is a liable protein and degraded by ubiquitin-proteasome system. Although several E3 ubiquitin ligases for Snail degradation have been identified (31)(32)(33), the DUBs for the stabilization of Snail remain less defined. In this study, we identified USP3 serves as a bona fide DUB mediating Snail stabilization.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail

Fan

Chen

et al. 2019

Molecular Cancer Research

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Epithelial-mesenchymal transition (EMT) represents one of the most important events in the invasion of glioblastomas (GBM); therefore, better understanding of mechanisms that govern EMT is crucial for the treatment of GBMs. In this study, we report that the deubiquitinase ubiquitinspecific protease 3 (USP3) is significantly upregulated in GBMs and correlates with a shorter median overall and relapse-free survival. Silencing of USP3 attenuates the migration and invasion abilities of GBM cells in vitro and tumor growth in an orthotopic xenograft mouse model. Mechanistically, we identify USP3 as a bona fide deubiquitinase for Snail, a master transcription factor that promotes EMT, in GBM cells. USP3 interacts directly with Snail and stabilizes Snail via deubiquitination. Ectopic expression of Snail could largely rescue the inhibitory effects of USP3 depletion on migration, invasion, and tumor growth of GBM cells. In addition, we found that USP3 strongly correlates with Snail expression in primary human GBM samples. Overall, our findings reveal a critical USP3-Snail signaling axis in EMT and invasion, and provide an effective therapeutic approach against GBM. Implications:Our study establishes USP3-mediated Snail stabilization as an important mechanism underlying GBM invasion and progression, and provides a rationale for potential therapeutic interventions in the treatment of GBM.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail

Fan

Chen

et al. 2019

Molecular Cancer Research

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“…In doing so, Brg1 functions as a chromosome modifier, affecting several gene sets associated with cell migration and cell mobility 41 . During the peer-review of this paper, a report about FBW7 directly regulating the ubiquitination and proteolysis of Snail in NSCLC (non-small-cell lung cancer) cells 42 prompted us to further analyze which plays more critical role in the EMT regulation by FBW7. In Supplementary Figure 12b and c, we could observe the increased migration induced by Brg1 overexpression was significantly rescued by Snail knockdown, but not to the normal level (EV group), which means except Snail, other Brg1 targets including the reported E-cadherin that participate in regulating cell migration and tumor metastasis in the gastric cancer setting requires further exploration.…”

Section: Discussionmentioning

confidence: 99%

SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis

et al. 2018

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Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCFFBW7. We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. In keeping with a tumor suppressive role of FBW7 in human gastric cancer, we find an inverse correlation between FBW7 and Brg1 expression in human gastric cancer clinical samples. Mechanistically, we find that stabilization of Brg1 in gastric cancer cells suppresses E-cadherin expression, subsequently promoting gastric cancer metastasis. Hence, this previously unknown FBW7/Brg1 signaling axis provides the molecular basis and the rationale to target Brg1 in FBW7-compromised human gastric cancers.

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“…E-cadherin suppresses initiation and epithelial-mesenchymal transition (EMT) in early-stage gastric carcinogenesis 16,17 . Previous studies indicated that loss of F-box and WD-repeat domaincontaining 7 (FBW7) induced EMT in cancers 18,19 . The Snai1 transcriptionally represses E-cadherin and promotes tumor proliferation and invasion 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR −/− ) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR +/ mice (K19-Wnt1/C2mE x FIR +/− ). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR +/− mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.

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FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein

Cited by 49 publications

References 28 publications

Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail

Ubiquitin-Specific Protease 3 Promotes Glioblastoma Cell Invasion and Epithelial–Mesenchymal Transition via Stabilizing Snail

SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

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