Abstract
Cancer stem cells (CSCs) are regarded as the root of tumor recurrence and distant metastasis, as well as the major cause of resistance to conventional cancer therapies. Elucidating the mechanism of regulating CSCs is of great significance for the development of CSCs-targeting therapy strategies. YAP/TAZ are identified as key regulators of CSCs-related traits on breast cancer cells; however, the upstream regulatory mechanism of Hippo kinases cascade involved in regulating YAP/TAZ remains elusive. In this study, we found that the low expression of RICH1 in breast cancer was associated with poor prognosis. Depletion of RICH1 promoted the stemness and disrupted the normal epithelial architecture of MCF10A cells. Besides, RICH1 inhibited the migration and invasion of breast cancer cells and sensitized these cells to chemotherapeutic drugs. Mechanistically, RICH1 activated the kinases cascade of Hippo signaling via displacing Amot-p80 from the complex with Merlin. Further studies revealed that the deletion of the BAR domain of RICH1 abolished the function of attenuating the binding of Amot-p80 and Merlin, illustrating that the competitive binding to Amot-p80 with Merlin was mediated by the BAR domain of RICH1. In conclusion, our work elucidated the role and molecular mechanism of RICH1 in stemness regulation of breast cancer, and might provide opportunities for CSCs-targeting therapy.
Highlights
Breast cancer is the most common cancer in the world [1]. the clinical application of a variety of new therapeutic regimens has significantly improved the prognosis of breast cancer patients, there are still a majority of patients inevitably suffering from disease recurrence or metastasis
We revealed that the low expression of that RICH1 might play a negative regulatory role in breast cancer stem-like cells (BCSCs)
Low expression of RICH1 is associated with poor prognosis in were established using RICH1-targeted lentivirus (Fig. 3A), breast cancer patients To investigate the role of RICH1 in breast cancer, we downloaded followed by flow cytometry analysis of Cancer stem cells (CSCs) contents in these cell lines
Summary
Breast cancer is the most common cancer in the world [1]. the clinical application of a variety of new therapeutic regimens has significantly improved the prognosis of breast cancer patients, there are still a majority of patients inevitably suffering from disease recurrence or metastasis. In addition to regulating Rho and found that RICH1 was significantly down-regulated in cancer signaling, RICH1 is involved in the formation of tight junctions and maintenance of apical-basal polarity of epithelial cells, by anchoring to the Crumbs complex (composed of CRB, PALS1, and mammospheres (Fig. 2A). To ensure the clinical relevance of involved in the maintenance of apical-basal polarity of epithelial BCSC-associated marker and RICH1, we assessed the expression of cells MDCK by regulating the GTPase activity of Cdc; Yi et al [20] RICH1 and ALDH1A1 by IHC in 30 breast cancer samples. RICH1 overexpression could activate the kinases cascade of Hippo signaling by competing with Merlin for binding RICH1 inhibits stem cell-like properties in breast cancer and to Amot-p80, which further inhibits stemness and improve the maintains the normal epithelial architecture of MCF10A cells chemosensitivity of breast cancer cells. MCF10A with RICH1 knockdown (MCF10A-shRICH1-1 and MCF10A-shRICH1-2), and breast cancer cells SUM159 and BT549
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