Apical–basal polarity inhibits epithelial–mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation

Jung, Hae-Yun; Fattet, Laurent; Tsai, Jeff H.; Kajimoto, Tetsuya; Chang, Qiang; Newton, Alexandra C.; Yang, Jing

doi:10.1038/s41556-019-0291-8

Cited by 103 publications

(89 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Snail is an important EMT-inducing transcription factor and is closely correlated with invasion and metastasis in diverse solid tumors (27)(28)(29)(30). Snail is a liable protein and degraded by ubiquitin-proteasome system.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…By contrast, the closely related members of the proton-sensing GPCR family GPR4 and GPR65 did not have similar effects on overall survival (Supplemental 5). To ascertain if GPR68 and its variant could modulate metastatic potential in breast cancer in vitro we utilized spheroid integrity and invasion assay (Gayan et al, 2017;Jung et al, 2019) . Transient transfection in MCF7 cells of GFP, GPR68-GFP, 336X-GFP reveals that, 3 days post matrix addition the continuity of the outer ring of cells becomes disrupted by the inner core in GPR68-GFP and 336X-GFP transected spheroids ( Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Coupling Metastasis to pH-Sensing GPR68 Using a Novel Small Molecule Inhibitor

Williams

Neitzel

Karki

et al. 2019

Preprint

View full text Add to dashboard Cite

Acidic milieu is a hallmark of glycolytic metabolism which occurs in cancerous cells. The effect of the acidic environment on cancer progression can be categorized into effects on tumor cell survival, tumor metastasis, inflammatory response, and blood vessels. Yet the underlying signaling and cell biological underpinnings of these phenomena are not well understood. Here, we describe, ogremorphen, a first-in-class inhibitor of proton-sensing GPCR GPR68. Discovered from a chemical genetic zebrafish screen, ogremorphen perturbed neural crest migration. Furthermore, ogremorphen was shown to inhibit migration in a number of human melanoma lines, which derive from the neural crest. Phenome-wide association study identified a natural variant that is aberrantly active and is associated with metastasis of common cancers. Our study suggests that GPR68 activity is associated with an increased ability for cancer cell migration and contributes to metastasis.

show abstract

“…In addition, we observed that MK5-AS1 could positively regulate SNAI1 and MK5 mRNA and protein expression. Over the last decade, research studies have focused on inhibiting or even reversing SNAI1induced EMT, including a series of cell morphological conversions, changes in extracellular matrix properties, and redistribution of surface markers on membranes [37,38]. Nevertheless, most trials with SNAI1 inhibitors have not been optimistic, which could be attributed, at least in part, to suboptimal target selection.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

Yang

Chen

Shi

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Long noncoding RNAs (lncRNAs) are considered critical regulators in cancers; however, the clinical significance and mechanisms of MAPKAPK5-AS1 (hereinafter referred to as MK5-AS1) in colorectal cancer (CRC) remain mostly unknown. Methods: In this study, quantitative real-time PCR ( qPCR ) and western blotting were utilized to detect the levels of MK5-AS1, let-7f-1-3p and MK5 (MAPK activated protein kinase 5) in CRC tissues and cell lines. The biological functions of MK5-AS1, let-7f-1-3p and MK5 in CRC cells were explored using Cell Counting Kit-8 ( CCK8 ), colony formation and transwell assays. The potential mechanisms of MK5-AS1 were evaluated by RNA pull-down, RNA immunoprecipitation ( RIP ), dual luciferase reporter assay, chromatin immunoprecipitation ( CHIP ) and bioinformatics analysis. The effects of MK5-AS1 and MK5 on CRC were investigated by a xenotransplantation model. Results : We confirmed that MK5-AS1 was significantly increased in CRC tissues. Knockdown of MK5-AS1 suppressed cell migration and invasion in vitro and inhibited lung metastasis in mice. Mechanistically, MK5-AS1 regulated SNAI1 expression by sponging let-7f-1-3p and cis -regulated the adjacent gene MK5. Moreover, MK5-AS1 recruited RBM4 and eIF4A1 to promote the translation of MK5. Our study verified that MK5 promoted the phosphorylation of c-Jun, which activated the transcription of SNAI1 by directly binding to its promoter. Conclusions : MK5-AS1 cis -regulated the nearby gene MK5 and acted as a let-7f-1-3p sponge, playing a vital role in CRC tumorigenesis. This study could provide novel insights into molecular therapeutic targets of CRC.

show abstract

Apical–basal polarity inhibits epithelial–mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation

Cited by 103 publications

References 56 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

Coupling Metastasis to pH-Sensing GPR68 Using a Novel Small Molecule Inhibitor

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

Contact Info

Product

Resources

About