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Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival

Abstract

MCL1 is essential for the survival of stem and progenitor cells of multiple lineages1,2, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases3,4,5,6. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma7,8,9, 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.

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Figure 1: USP9X binds MCL1.
Figure 2: USP9X overexpression in tumours correlates with increased MCL1 protein expression and poor prognosis.
Figure 3: USP9X deubiquitinates MCL1 and regulates its degradation.
Figure 4: DNA damage negates USP9X inhibition of MCL1-regulated cell death.

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Acknowledgements

We thank J. Cupp, W. Tombo, B. Yang, L. Gilmour, J.-A. Hongo, R. Vij, C. Quan, M. Vasser, P. Ng, W. Sandoval and T. Huang for technical assistance; B. Bolon for immunohistochemical scoring; S. Johnson for patient data acquisition; and K. Newton for manuscript preparation.

Author Contributions V.M.D. directed the study; M.S. and X.H., with assistance from K.O. and F.B., conducted all biochemical experiments; J.R.L. ran the mass spectrometry; J.L., P.Y. and D.D. performed bioinformatics analyses; R.F., J.E.-A. and D.M.F. generated the immunohistochemical data; H.M. ran the xenograft study; D.C.S.H. contributed to experiment design.

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Correspondence to Vishva M. Dixit.

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All authors were employees of or consultants to Genentech, Inc.

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Schwickart, M., Huang, X., Lill, J. et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103–107 (2010). https://doi.org/10.1038/nature08646

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