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Article: SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression

TitleSCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression
Authors
KeywordsHepatocellular carcinoma
Metastasis
Protein stability
ROCK2
SCYL3
Issue Date1-Jan-2023
PublisherElsevier
Citation
JHEP Reports, 2023, v. 5, n. 1 How to Cite?
Abstract

Background & Aims

SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC).

Methods

The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. In vivo tumor progression was evaluated in Tp53KO/c-MycOE mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining.

Results

SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as in vivo metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in Tp53KO/c-MycOE mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions.

Conclusions

These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC.

Impact and implications

SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients.


Persistent Identifierhttp://hdl.handle.net/10722/331734
ISSN
2023 Impact Factor: 9.5
2023 SCImago Journal Rankings: 3.409
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLei, MML-
dc.contributor.authorLeung, CON-
dc.contributor.authorLau, EYT-
dc.contributor.authorLeung, RWH-
dc.contributor.authorMa, VWS-
dc.contributor.authorTong, M-
dc.contributor.authorLu, YY-
dc.contributor.authorHuang, CY-
dc.contributor.authorZhu, QH-
dc.contributor.authorNg, IOL-
dc.contributor.authorMa, SKY-
dc.contributor.authorLee, TKW-
dc.date.accessioned2023-09-21T06:58:27Z-
dc.date.available2023-09-21T06:58:27Z-
dc.date.issued2023-01-01-
dc.identifier.citationJHEP Reports, 2023, v. 5, n. 1-
dc.identifier.issn2589-5559-
dc.identifier.urihttp://hdl.handle.net/10722/331734-
dc.description.abstract<h3>Background & Aims</h3><p>SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC).</p><h3>Methods</h3><p>The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. <em>In vivo</em> tumor progression was evaluated in <em>Tp53</em><sup>KO</sup>/<em>c-Myc</em><sup>OE</sup> mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining.</p><h3>Results</h3><p>SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as <em>in vivo</em> metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in <em>Tp53</em><sup>KO</sup>/<em>c-Myc</em><sup>OE</sup> mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions.</p><h3>Conclusions</h3><p>These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC.</p><h3>Impact and implications</h3><p>SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofJHEP Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectHepatocellular carcinoma-
dc.subjectMetastasis-
dc.subjectProtein stability-
dc.subjectROCK2-
dc.subjectSCYL3-
dc.titleSCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression-
dc.typeArticle-
dc.identifier.doi10.1016/j.jhepr.2022.100604-
dc.identifier.scopuseid_2-s2.0-85142434453-
dc.identifier.volume5-
dc.identifier.issue1-
dc.identifier.eissn2589-5559-
dc.identifier.isiWOS:001029619700001-
dc.identifier.issnl2589-5559-

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