Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival.
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.
Schwickart
Martin
M
Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Huang
Xiaodong
X
Lill
Jennie R
JR
Liu
Jinfeng
J
Ferrando
Ronald
R
French
Dorothy M
DM
Maecker
Heather
H
O'Rourke
Karen
K
Bazan
Fernando
F
Eastham-Anderson
Jeffrey
J
Yue
Peng
P
Dornan
David
D
Huang
David C S
DC
Dixit
Vishva M
VM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D000077143:Docetaxel; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006207:Half-Life; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology; D010766:Phosphorylation / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding / Q000528:radiation effects; D055550:Protein Stability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014466:Ultraviolet Rays; D023041:Xenograft Model Antitumor Assays
C501332:ABT-737; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D043823:Taxoids; C506234:USP9X protein, human; D025821:Polyubiquitin; D000077143:Docetaxel; D005047:Etoposide; D043222:Ubiquitin Thiolesterase; D008239:Lysine