Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival

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.

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

“…3 On the basis of our findings, Ku70 may have a similar role as USP9X in regulating Mcl-1 stability. To test this possibility, H1299 cells were transfected with Ku70 short hairpin RNA (shRNA), USP9X shRNA or their combination in the absence or presence of MG132.…”

“…Mcl-1 is an antiapoptotic molecule that is overexpressed in various types of cancers, including lung cancer, 1 leukemia, 2 lymphoma, 3 hepatocellular carcinoma 4 and so on. In addition to its antiapoptotic function, Mcl-1 is also an oncoprotein that promotes the development of cancer.…”

“…9,10 Inversely, USP9X has been demonstrated as the Mcl-1 deubiquitinase that removes the Lys 48-linked polyubiquitin chains that normally mark Mcl-1 for proteasomal degradation, leading to stabilization of Mcl-1. 3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair.…”

“…3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. [12][13][14][15] The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains.…”

Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin‐specific peptidase 9, X‐linked in oral squamous cell carcinoma

“…USP9X is expressed abnormally in nonsmall cell lung cancer, breast cancer, melanoma, head and neck SCC, and other human malignancies 16, 17, 18, 19. USP9X regulates the ubiquitination of its target protein by ubiquitin‐specific protease activity, thereby affecting the expression level 20. Therefore, USP9X has become a potential target for tumor therapy.…”