Transcriptional repressor Snail is a master regulator of epithelial–mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. Cancer Res; 74(16); 4353-63. ©2014 AACR

Accurate descriptions of strength evolution are required in predictive models of fault zone behavior during earthquakes. At low sliding rates, frictional resistance between fault rocks is much higher than the shear stress that is typically inferred to be present during earthquakes. Laboratory experiments confirm that the friction coefficient drops at high sliding rates, and it is suggested that strengthening, possibly related to an increase in the area of viscous melt patches, may occur after this initial weakening stage. Most existing weakening mechanisms do not predict such strengthening, which may exert an important control on the thickness of the shear zone. We propose a micromechanical model of flash heating that describes how shear resistance evolves at the asperity scale as a result of distributed deformation over a weak layer that grows during the brief lifetime of each asperity contact. Beyond a threshold weakening velocity, our model predicts that friction should decrease with slip rate since higher sliding speeds cause the weak layer to thicken more rapidly. A comparison with published experimental data from a range of mineral systems shows good agreement with the model predictions. The parameter choices that ensure good model fits to the laboratory friction data are consistent with a priori estimates for the onset of asperity melting at high contact normal stresses. At higher sliding rates and/or elevated temperatures, our model predicts that the frictional rate dependence should transition from velocity weakening to become velocity strengthening because decreases in the contact lifetime with slip rate cause the average asperity strength to increase.

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