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Title: | SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression | Authors: | Lei, MML Leung, CON Lau, EYT Leung, RWH Ma, VWS Tong, M Lu, YY Huang, CY Zhu, QH Ng, IOL Ma, SPN Lee, TKW |
Issue Date: | Jan-2023 | Source: | JHEP reports, Jan. 2023, v. 5, no. 1, 100604 | 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 inhouse 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. | Keywords: | SCYL3 ROCK2 Hepatocellular carcinoma Protein stability Metastasis |
Publisher: | Elsevier BV | Journal: | JHEP reports | EISSN: | 2589-5559 | DOI: | 10.1016/j.jhepr.2022.100604 | Rights: | © 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The following publication Lei, M. M. L., Leung, C. O. N., Lau, E. Y. T., Leung, R. W. H., Ma, V. W. S., Tong, M., Lu, Y. Y., Huang, C. Y., Zhu, Q. H., Ng, I. O. L., Ma, S., & Lee, T. K. W. (2023). SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression. JHEP Reports, 5(1), 100604 is available at https://dx.doi.org/10.1016/j.jhepr.2022.100604. |
Appears in Collections: | Journal/Magazine Article |
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