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The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development.

Objective Euthanasia or physician-assisted suicide (EAS) of psychiatric patients is legal in some countries but remains controversial. This study examined a frequently raised concern about the practice: how physicians address the issue of decision-making capacity of persons requesting psychiatric EAS. Methods A review of psychiatric EAS case summaries published by the Dutch Regional Euthanasia Review Committees. Directed content analysis using a capacity-specific 4 abilities model (understanding of facts, applying those facts to self, weighing/reasoning, and evidencing choice) was used to code texts discussing capacity. 66 cases from 2011-2014 were reviewed. Results In 55% (36 of 66) of cases the capacity-specific discussion consisted of only global judgments of patients’ capacity, even in patients with psychotic disorders. 32% (21 of 66) of cases included evidentiary statements regarding capacity-specific abilities; only 5 cases (8%) mentioned all four abilities. Physicians frequently stated that psychosis or depression did or did not impact capacity but provided little explanation regarding their judgments. Physicians in 8 cases (12%) disagreed about capacity; even when no explanation is given for the disagreement, the review committees generally accepted the judgment of the physician performing EAS. In one case, the physicians noted that not all capacity-specific abilities were intact but deemed the patient capable. Conclusion Case summaries of psychiatric EAS in the Netherlands do not show that a high threshold of capacity is required for granting EAS. Although this may reflect limitations in documentation, it likely represents a practice that reflects the normative position of the review committees.

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