11 research outputs found
A covalently bound inhibitor triggers EZH2 degradation through CHIPâmediated ubiquitination
Abstract Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2â and methyltransferaseâindependent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2âtargeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2âSET domain, triggering EZH2 degradation through COOH terminus of Hsp70âinteracting protein (CHIP)âmediated ubiquitination. This class of inhibitors significantly suppressed H3K27Me3 and effectively reactivated polycomb repressor complex 2 (PRC2)âsilenced tumor suppressor genes. Moreover, the novel inhibitors significantly suppressed tumor growth in an EZH2âdependent manner, and tumors bearing a nonâGNAâinteracting C668SâEZH2 mutation exhibited resistance to the inhibitors. Together, our results identify the inhibition of the signaling pathway that governs GNAâmediated destruction of EZH2 as a promising antiâcancer strategy
Performance and mechanism research of hierarchically structured Li-rich cathode materials for advanced lithiumâion batteries
The hierarchically structured cathode material Li1.165Mn0.501Ni0.167Co0.167O2 (LMNCO) is successfully synthesized via a facile ultrasonic-assisted co-precipitation method with a two-step heat treatment by adopting graphene and carbon nanotubes (CNTs) as functional framework and modified material. The structure and electrochemical performance degeneration mechanism were systematically investigated in this work. The obtained LMNCO microspheres possess a hierarchical nano-micropore structure assembled with nanosized building blocks, which originates from the oxidative decomposition of the transition metal carbonate precursor and carbonaceous materials accompanied with the release of CO2 (but still remain carbon residue). Whatâs more, the positive electrode exhibits enhanced specific capacities (276.6 mAh gâ1 at 0.1 C), superior initial coulombic efficiency (80.3 %), remarkable rate capability (60.5 mAh gâ1 at 10 C) and high Li+ diffusion coefficient (~10â9 cm2 sâ1). The excellent performances can be attributed to the pore structure, small particle sizes, large specific surface area and enhanced electrical conductivity. (1 C = 250 mA gâ1).Department of Electrical Engineerin