Abstract
Triple-negative breast cancer (TNBC) is extremely aggressive and lacks effective therapy. SAM and SH3 domain containing1 (SASH1) has been implicated in TNBC as a candidate tumor suppressor; however, the mechanisms of action of SASH1 in TNBC remain underexplored. Here, we show that SASH1 was significantly downregulated in TNBC patients samples compared with other subtypes of breast cancer. Ectopic SASH1 expression inhibited, while depletion of SASH1 enhanced, the invasive phenotype of TNBC cells, accompanied by deregulated expression of MMP2 and MMP9. The functional effects of SASH1 depletion were confirmed in the chicken chorioallantoic membrane and mouse xenograft models. Mechanistically, SASH1 knockdown downregulated the phosphorylation levels of the Hippo kinase LATS1 and its effector YAP (Yes associated protein), thereby upregulating YAP accumulation together with its downstream target CYR61. Consistently, forced SASH1 expression exhibited opposite effects. Pharmacological inhibition of YAP or knockdown of YAP reversed the enhanced cell invasion of TNBC cells following SASH1 depletion. Furthermore, SASH1-induced YAP signaling was LATS1-dependent, which in reverse enhanced phosphorylation of SASH1. The SASH1 S407A mutant (phosphorylation deficient) failed to rescue the altered YAP signaling by SASH1 knockdown. Notably, SASH1 depletion upregulated ARHGAP42 levels via YAP-TEAD and the YAP-ARHGAP42-actin axis contributed to SASH1-regulated TNBC cell invasion. Therefore, our findings uncover a new mechanism for the tumor-suppressive activity of SASH1 in TNBC, which may serve as a novel target for therapeutic intervention.
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Acknowledgements
We thank professors Bin Zhao, Huadong Pei, Shian Wu, Zengqiang Yuan and Alexander Hergovich for providing plasmids. The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (81572707 and 81772973 to SM, 81973646 to PG, 81402071 to DL).
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SM, YM, SS, and PG conceived and designed the study. KJ, PL, and HX performed the major experiments and analyzed the data, SM, KJ, and DL wrote and edited the paper. SD and WC performed cellular experiments and took part in confocal experiments. DL performed the bioinformatics analysis and the statistical analysis. KJ, KF, and XZ contributed to animal experiments and carried out the data analyses. LY and TL sectioned paraffin-embedded patient samples. KJ and DL revised the paper. All authors read and approved the final paper.
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Jiang, K., Liu, P., Xu, H. et al. SASH1 suppresses triple-negative breast cancer cell invasion through YAP-ARHGAP42-actin axis. Oncogene 39, 5015–5030 (2020). https://doi.org/10.1038/s41388-020-1356-7
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DOI: https://doi.org/10.1038/s41388-020-1356-7
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