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- Title
Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival.
- Authors
Schwickart, Martin; XiaoDong Huang; Lill, Jennie R.; Jinfeng Liu; Ferrando, Ronald; French, Dorothy M.; Maecker, Heather; O'Rourke, Karen; Bazan, Fernando; Eastham-Anderson, Jeffrey; Peng Yue; Dornan, David; Huang, David C. S.; Dixit, Vishva M.
- Abstract
MCL1 is essential for the survival of stem and progenitor cells of multiple lineages, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.
- Subjects
LYMPHOMAS; LYMPHOPROLIFERATIVE disorders; MULTIPLE myeloma; CANCER cells; LIGASES; LEUKEMIA; CELL death; TUMOR proteins; CANCER patients
- Publication
Nature, 2010, Vol 463, Issue 7277, p103
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature08646