The E3 Ubiquitin Ligase HectD1 Suppresses EMT and Metastasis by Targeting the +TIP ACF7 for Degradation

• Published in: Cell reports (Cambridge) 2018-01, Vol.22 (4), p.1016-1030
• Main Authors: Duhamel, Stéphanie, Goyette, Marie-Anne, Thibault, Marie-Pier, Filion, Dominic, Gaboury, Louis, Côté, Jean-François
• Format: Article
• Language: English
• Subjects: ACF7; breast cancer; EMT; epithelial-to-mesenchymal transition; HectD1; invasion; metastasis; microtubule plus-end tracking proteins; migration; ubiquitinylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.12.096

Cancer cells exploit the epithelial-to-mesenchymal transition (EMT) program to become metastatic. Cytoskeletal regulators are required in mesenchymal cells where they promote EMT and EMT-induced migration. In a search for regulators of metastasis, we conducted shRNA screens targeting the microtubule plus-end tracking proteins (+TIPs). We show that the +TIP ACF7 is essential both for the maintenance of the EMT program and to promote migration. We find that the E3 ubiquitin ligase HectD1 promotes ACF7-proteasome-mediated degradation. Depletion of HectD1 stabilized ACF7, and this enhanced EMT and migration. Decreased HectD1 expression increased metastases in mouse models and conferred increased resistance to the cytotoxic drug cisplatin. A retrospective analysis of biopsies from breast cancer patients also reveals a correlation between higher ACF7 or lower HectD1 expression with poor clinical outcomes. Together, these results suggest that the control of ACF7 levels by HectD1 modulates EMT and the efficiency of metastasis. [Display omitted] •Functional screens show that ACF7 is required for cell migration and to sustain EMT•The E3 ubiquitin ligase HectD1 targets ACF7 for ubiquitination and degradation•Depletion of HectD1 promotes ACF7-induced EMT, invasion, and experimental metastasis•HectD1 levels inversely relate to ACF7 levels, EMT, and cancer patient outcome The epithelial-to-mesenchymal transition is fundamental to metastasis. Duhamel et al. report that ACF7 is required for EMT maintenance, cell migration, and metastasis. HectD1 is identified as a potent regulator of ACF7 protein levels. Targeting the HectD1/ACF7 signaling axis may offer a therapeutic opportunity to limit metastasis.