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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References
Opferman, J. T. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003)
Opferman, J. T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Science 307, 1101–1104 (2005)
Zhao, Y. et al. Glycogen synthase kinase 3α and 3β mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol. Cell. Biol. 27, 4328–4339 (2007)
Zhong, Q. et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005)
Nijhawan, D. et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 17, 1475–1486 (2003)
van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006)
Kitada, S. et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 91, 3379–3389 (1998)
Warr, M. R. & Shore, G. C. Unique biology of Mcl-1: therapeutic opportunities in cancer. Curr. Mol. Med. 8, 138–147 (2008)
Wuillème-Toumi, S. et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia 19, 1248–1252 (2005)
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000)
Wood, S. A. et al. Cloning and expression analysis of a novel mouse gene with sequence similarity to the Drosophila fat facets gene. Mech. Dev. 63, 29–38 (1997)
Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000)
Wang, J. M., Lai, M. Z. & Yang-Yen, H. F. Interleukin-3 stimulation of mcl-1 gene transcription involves activation of the PU.1 transcription factor through a p38 mitogen-activated protein kinase-dependent pathway. Mol. Cell. Biol. 23, 1896–1909 (2003)
Hummel, M. et al. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N. Engl. J. Med. 354, 2419–2430 (2006)
Carrasco, D. R. et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9, 313–325 (2006)
Zhan, F. et al. The molecular classification of multiple myeloma. Blood 108, 2020–2028 (2006)
Mouchantaf, R. et al. The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X. J. Biol. Chem. 281, 38738–38747 (2006)
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998)
Ding, Q. et al. Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res. 68, 6109–6117 (2008)
Domina, A. M. et al. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23, 5301–5315 (2004)
Maurer, U. et al. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol. Cell 21, 749–760 (2006)
Ding, Q. et al. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3β activity and associates with poor prognosis in human breast cancer. Cancer Res. 67, 4564–4571 (2007)
Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005)
Tahir, S. K. et al. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 67, 1176–1183 (2007)
Cuconati, A. et al. DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev. 17, 2922–2932 (2003)
Jourdan, M. et al. A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells. Oncogene 22, 2950–2959 (2003)
Austin, M. & Cook, S. J. Increased expression of Mcl-1 is required for protection against serum starvation in phosphatase and tensin homologue on chromosome 10 null mouse embryonic fibroblasts, but repression of Bim is favored in human glioblastomas. J. Biol. Chem. 280, 33280–33288 (2005)
Kaufmann, S. H. et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood 91, 991–1000 (1998)
Huang, D. C., Cory, S. & Strasser, A. Bcl-2, Bcl-XL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. Oncogene 14, 405–414 (1997)
Newton, K. et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 134, 668–678 (2008)
Brey, E. M. et al. Automated selection of DAB-labeled tissue for immunohistochemical quantification. J. Histochem. Cytochem. 51, 575–584 (2003)
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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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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DOI: https://doi.org/10.1038/nature08646
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