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RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

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.

SUBMITTER: Radaszkiewicz T

PROVIDER: S-EPMC8550759 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

Radaszkiewicz Tomasz T Nosková Michaela M Gömöryová Kristína K Vondálová Blanářová Olga O Radaszkiewicz Katarzyna Anna KA Picková Markéta M Víchová Ráchel R Gybeľ Tomáš T Kaiser Karol K Demková Lucia L Kučerová Lucia L Bárta Tomáš T Potěšil David D Zdráhal Zbyněk Z Souček Karel K Bryja Vítězslav V

eLife 20211027

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-depend ...[more]

PMID: 34702444

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Project description:Tumor cells invade and spread via either a mesenchymal or an amoeboid mode of migration. Amoeboid tumor cells have a rounded morphology and pronounced RhoA activity. Here, we investigate how WNT5A signaling, a tumor promotor in melanoma, relates to Rho GTPase activity and amoeboid migration. We compared melanoma cells with low (HTB63 cells) and high (WM852 cells) WNT5A expression. HTB63 cells exhibited an amoeboid morphology and had higher RhoA activity but lower invasiveness than WM852 cells in a three-dimensional (3D) collagen matrix. We next explored the relationships between WNT5A, morphology, and invasive behavior. WNT5A knockdown impaired Rho GTPase Cdc42 activity, resulting in reduced invasion of amoeboid and mesenchymal melanoma cells. Interestingly, knockdown of WNT5A or inhibition of its secretion in WM852 cells expressing wild-type BRAF also led to increased RhoA activity via decreased RND3 expression, resulting in predominantly amoeboid morphology. In contrast, such treatments had the opposite effects on RND3 expression and RhoA activity in HTB63 cells expressing the active BRAFV600 mutation. However, treatment of HTB63 cells with a BRAF inhibitor made them respond to WNT5A knockdown in a similar manner as WM852 cells expressing wild-type BRAF. We next found that dual targeting of WNT5A and RhoA more effectively reduced melanoma cell invasion than targeting either protein individually. Taken together, our results suggest that low WNT5A signaling in melanoma cells promotes a rounded amoeboid type of invasion, which quite likely serves as a compensatory response to decreased WNT5A/Cdc42-driven invasion. This phenomenon partially explains the enduring melanoma cell invasion observed after impaired WNT5A signaling and has therapeutic implications. Our results suggest that dual targeting of WNT5A and RhoA signaling is a more effective strategy for controlling the invasion of BRAF wild-type and BRAFV600 mutated melanomas treated with a BRAF inhibitor than targeting either of the proteins individually.

Project description:Melanoma is the most lethal cutaneous cancer with a high metastatic rate worldwide, causing ~55,500 deaths annually. Although the selective B-Raf oncogene serine/threonine-kinase (BRAF) inhibitors, dabrafenib and vemurafenib, have been approved for the treatment of BRAF-mutant metastatic melanoma, the 5-year survival rate remains unfavorable due to acquired therapy resistance. Therefore, it is of great importance to develop alternative therapeutic drugs and uncover their mechanisms for the treatment of melanoma. 7-dehydrocholesterol (7-DHC) has been demonstrated to inhibit melanoma, but the mechanism is unclear. Therefore, the present study aimed to elucidate the mechanisms of the inhibitory effect of 7-DHC in melanoma cells via analyzing the proliferation, migration, apoptosis, cell cycle and transcriptional sequencing of melanoma cells treated with 7-DHC, as well as constructing a gene signature according to public data of patients with melanoma. In the present study, 7-DHC, the precursor of vitamin D3, was able to induce apoptosis and inhibit cell proliferation and invasion of melanoma cells in a dose-dependent manner. RNA sequencing of melanoma cells treated with different concentrations of 7-DHC revealed that, compared with untreated melanoma cells, 65 genes were downregulated, and genes involved in the regulation of NF-ĸB import into the nucleus and NF-ĸB signaling were significantly repressed. Consistently, the Akt kinase family was one of most common somatic mutation hotspots in patients with melanoma according to The Cancer Genome Atlas enrichment analysis. Furthermore, 7-DHC decreased the phosphorylation of Akt1-Ser473 rather than that of MEK1, and the decreased phosphorylation of Akt1 subsequently inhibited the translocation of free RELA proto-oncogene NF-κB subunit to the nucleus. Finally, by intersecting downregulated genes by 7-DHC treatment and upregulated genes in patients with melanoma, a 7-DHC gene signature was identified, which was negatively associated with the prognosis. Overall, the present results demonstrated that 7-DHC suppressed melanoma cell proliferation and invasion via the Akt1/NF-ĸB signaling pathway, and 7-DHC key target genes were negatively associated with the prognosis. These findings highlight the potential application of 7-DHC for the treatment of melanoma in the future.

Dataset Information

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

Publications

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

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