2021
Radaszkiewicz, Tomasz; Nosková, Michaela; Gömöryová, Kristína; Blanářová, Olga Vondálová; Radaszkiewicz, Katarzyna Anna; Picková, Markéta; Víchová, Ráchel; Gybeľ, Tomáš; Kaiser, Karol; Demková, Lucia; Kučerová, Lucia; Bárta, Tomáš; Potěšil, David; Zdráhal, Zbyněk; Souček, Karel; Bryja, Vítězslav
RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. Journal Article
In: eLife, vol. 10, 2021, ISSN: 2050-084X, (Place: England).
Abstract | Links | BibTeX | Tags: *Melanoma/genetics/pathology/prevention & control, *Signal Transduction, Animals, BRAF V600E, cancer biology, cell biology, human, Inbred NOD, Male, Melanoma, Mice, mouse, Neoplasm Invasiveness/genetics, RNF43, ROR1, Ubiquitin-Protein Ligases/*genetics/metabolism, VANGL1, Wnt-5a Protein/*genetics/metabolism, WNT5A
@article{radaszkiewicz_rnf43_2021,
title = {RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.},
author = {Tomasz Radaszkiewicz and Michaela Nosková and Kristína Gömöryová and Olga Vondálová Blanářová and Katarzyna Anna Radaszkiewicz and Markéta Picková and Ráchel Víchová and Tomáš Gybeľ and Karol Kaiser and Lucia Demková and Lucia Kučerová and Tomáš Bárta and David Potěšil and Zbyněk Zdráhal and Karel Souček and Vítězslav Bryja},
doi = {10.7554/eLife.65759},
issn = {2050-084X},
year = {2021},
date = {2021-10-01},
journal = {eLife},
volume = {10},
abstract = {RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.},
note = {Place: England},
keywords = {*Melanoma/genetics/pathology/prevention & control, *Signal Transduction, Animals, BRAF V600E, cancer biology, cell biology, human, Inbred NOD, Male, Melanoma, Mice, mouse, Neoplasm Invasiveness/genetics, RNF43, ROR1, Ubiquitin-Protein Ligases/*genetics/metabolism, VANGL1, Wnt-5a Protein/*genetics/metabolism, WNT5A},
pubstate = {published},
tppubtype = {article}
}
RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.
2011
Slabáková, Eva; Pernicová, Zuzana; Slavíčková, Eva; Staršíchová, Andrea; Kozubík, Alois; Souček, Karel
TGF-β1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. Journal Article
In: The Prostate, vol. 71, no. 12, pp. 1332–1343, 2011, ISSN: 1097-0045 0270-4137, (Place: United States).
Abstract | Links | BibTeX | Tags: *Epithelial-Mesenchymal Transition/genetics, Biomarkers/metabolism, Cell Line, Cell Movement, Homeodomain Proteins/genetics, Humans, Kinetics, Male, Messenger/metabolism, MicroRNAs/metabolism, Neoplasm Invasiveness/genetics, Phenotype, Prostatic Hyperplasia/*physiopathology, Repressor Proteins/genetics, RNA, Snail Family Transcription Factors, Transcription Factors/*biosynthesis/genetics, Transforming Growth Factor beta1/*pharmacology, Up-Regulation/drug effects, Vimentin/metabolism, Zinc Finger E-box Binding Homeobox 2, Zinc Finger E-box-Binding Homeobox 1
@article{slabakova_tgf-1-induced_2011,
title = {TGF-β1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug.},
author = {Eva Slabáková and Zuzana Pernicová and Eva Slavíčková and Andrea Staršíchová and Alois Kozubík and Karel Souček},
doi = {10.1002/pros.21350},
issn = {1097-0045 0270-4137},
year = {2011},
date = {2011-09-01},
journal = {The Prostate},
volume = {71},
number = {12},
pages = {1332–1343},
abstract = {BACKGROUND: Epithelial-mesenchymal transition (EMT) underlying cancer cell invasion and metastasis has been thoroughly studied in prostate cancer. Although EMT markers have been clinically observed in benign prostate hyperplasia, molecular events underlying the onset and progression of EMT in benign prostate cells have not been described. METHODS: EMT in BPH-1 cells was induced by TGF-β1 treatment and the kinetics of expression of EMT markers, regulators, and selected miRNAs was assessed by western blotting and quantitative RT-PCR. RESULTS: EMT in BPH-1 cells was accompanied by rapid up-regulation of SNAI2/Slug and ZEB1 transcription factors, while changes in expression levels of ZEB2 and miR-200 family members were observed after extended time intervals. Invasive phenotype with EMT hallmarks, characterizing tumorigenic clones derived from BPH-1 cells, was associated with increased mRNA levels of SNAI2, ZEB1, and ZEB2, but was not associated with significant changes in basal levels of miR-200 family members. RNA interference revealed that SNAI2/Slug is crucial for TGF-β1-induced vimentin up-regulation and migration of BPH-1 cells. CONCLUSIONS: This study suggests that in BPH-1 cells the transcription factor SNAI2/Slug is important for EMT initiation, while the ZEB family of transcription factors in cooperation with the miR-200 family may oppose the reversal of the EMT phenotype.},
note = {Place: United States},
keywords = {*Epithelial-Mesenchymal Transition/genetics, Biomarkers/metabolism, Cell Line, Cell Movement, Homeodomain Proteins/genetics, Humans, Kinetics, Male, Messenger/metabolism, MicroRNAs/metabolism, Neoplasm Invasiveness/genetics, Phenotype, Prostatic Hyperplasia/*physiopathology, Repressor Proteins/genetics, RNA, Snail Family Transcription Factors, Transcription Factors/*biosynthesis/genetics, Transforming Growth Factor beta1/*pharmacology, Up-Regulation/drug effects, Vimentin/metabolism, Zinc Finger E-box Binding Homeobox 2, Zinc Finger E-box-Binding Homeobox 1},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Epithelial-mesenchymal transition (EMT) underlying cancer cell invasion and metastasis has been thoroughly studied in prostate cancer. Although EMT markers have been clinically observed in benign prostate hyperplasia, molecular events underlying the onset and progression of EMT in benign prostate cells have not been described. METHODS: EMT in BPH-1 cells was induced by TGF-β1 treatment and the kinetics of expression of EMT markers, regulators, and selected miRNAs was assessed by western blotting and quantitative RT-PCR. RESULTS: EMT in BPH-1 cells was accompanied by rapid up-regulation of SNAI2/Slug and ZEB1 transcription factors, while changes in expression levels of ZEB2 and miR-200 family members were observed after extended time intervals. Invasive phenotype with EMT hallmarks, characterizing tumorigenic clones derived from BPH-1 cells, was associated with increased mRNA levels of SNAI2, ZEB1, and ZEB2, but was not associated with significant changes in basal levels of miR-200 family members. RNA interference revealed that SNAI2/Slug is crucial for TGF-β1-induced vimentin up-regulation and migration of BPH-1 cells. CONCLUSIONS: This study suggests that in BPH-1 cells the transcription factor SNAI2/Slug is important for EMT initiation, while the ZEB family of transcription factors in cooperation with the miR-200 family may oppose the reversal of the EMT phenotype.