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MGMT-Activated DUB3 Stabilizes MCL1 and Drives Chemoresistance in Ovarian Cancer

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MGMT-Activated DUB3 Stabilizes MCL1 and Drives Chemoresistance in Ovarian Cancer MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer Xiaowei Wua,1, Qingyu Luoa,1, Pengfei Zhaoa, Wan Changa, Yating Wangb, Tong Shub, Fang Dinga, Bin Lib, and Zhihua Liua,2 aState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academyof Medical Sciences and Peking Union Medical College, 100021 Beijing, China; and bDepartment of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China Edited by Junying Yuan, Harvard Medical School, Boston, MA, and approved January 4, 2019 (received for review August 29, 2018) Chemoresistance is a severe outcome among patients with ovarian (12), and sometimes functions as a tumor suppressor in certain bi- cancer that leads to a poor prognosis. MCL1 is an antiapoptotic ological processes and malignancies (13, 14). Similarly, USP13 acts as member of the BCL-2 family that has been found to play an essen- a tumor suppressor by stabilizing PTEN expression in breast cancer tial role in advancing chemoresistance and could be a promising (15). Moreover, neither USP9X nor USP13 could completely cleave target for the treatment of ovarian cancer. Here, we found that the ubiquitin chains on MCL1 in ubiquitination assays, suggesting deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates that other DUBs essential for MCL1 deubiquitination likely exist. MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 In this study, we identified that DUB3 is a critical deubiquitinase from degradation. Furthermore, we identified that O6-methylguanine- that stabilizes MCL1. We further showed that the 40th lysine DNA methyltransferase (MGMT) is a key activator of DUB3 tran- within the N terminus of MCL1 is mainly modified by DUB3. scription, and that the MGMT inhibitor PaTrin-2 effectively sup- Moreover, we revealed that PaTrin-2 is an effective small-molecule presses ovarian cancer cells with elevated MGMT-DUB3-MCL1 inhibitor (SMI) that suppresses DUB3 at the transcriptional expression both in vitro and in vivo. Most interestingly, we found level by targeting the DNA repair protein O6-methylguanine- that histone deacetylase inhibitors (HDACis) could significantly ac- DNA methyltransferase (MGMT). The in vitro and in vivo tivate MGMT/DUB3 expression; the combined administration of studies showed that the up-regulation of the MGMT-DUB3- HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, MCL1 signaling axis contributed to chemoresistance in ovarian CELL BIOLOGY our results revealed the essential role of the MGMT-DUB3-MCL1 cancer. In contrast, the depletion of DUB3 or administration of axis in the chemoresistance of ovarian cancer and identified that PaTrin-2 could significantly induce apoptosis in ovarian cancer a combined treatment with HDACis and PaTrin-2 is an effective cells via the down-regulation of MCL1. Interestingly, we ob- method for overcoming chemoresistance in ovarian cancer. served that histone deacetylase (HDAC) inhibitors (HDACis) could transcriptionally activate MGMT expression, which sensitized chemoresistance | DUB3 | MCL1 | MGMT | ovarian cancer the ovarian cancer cells to PaTrin-2. Our results provide a prom- ising therapeutic approach involving the combined administration varian cancer is the second most common and the most of HDACis and PaTrin-2 to overcome chemoresistance in ovarian Olethal gynecological malignancy worldwide, with a mortality cancer. rate exceeding 60%. According to one source of cancer statistics ∼ in China, 52,100 new cases and 22,500 deaths were related to Significance ovarian cancer in 2015 (1). In the United States, there will be an estimated 22,240 new cases and 14,070 deaths in 2018 (2). Ovarian cancer is the leading cause of death among gynecological Debulking surgery, followed by platinum/paclitaxel-based che- malignancies and has a poor prognosis characterized by resistance motherapy, is the standard treatment for patients with ovarian to chemotherapy. MCL1 has been found to play an essential role cancer. However, most patients relapse with chemoresistance af- in chemoresistance and could be a promising therapeutic target. ter prolonged chemotherapy administration. The B-cell lym- However, designing specific inhibitors targeting MCL1 remains phoma 2 (BCL-2) family encodes more than 20 proteins, including challenging. Here, we found that deubiquitinating enzyme 3 proapoptotic and antiapoptotic proteins that regulate the intrinsic (DUB3) stabilizes MCL1 via deubiquitination. We identified that O6- apoptosis pathway, which maintains the balance between cell methylguanine-DNA methyltransferase (MGMT) is a key activator survival and cell death (3). The up-regulation of the antiapoptotic of DUB3 transcription and that the MGMT inhibitor PaTrin-2 ef- BCL-2 family members has been recognized as essential for tu- fectively suppresses ovarian cancer cells with elevated MGMT- mors to evade chemotherapy and become drug resistant (4). Be- DUB3-MCL1 expression. We further showed that histone deace- cause of its short half-life, MCL1 is distinct from the other BCL-2 tylase (HDAC) inhibitors could significantly activate MGMT/DUB3 family members, providing a tactic for cells to switch to either expression to sensitize ovarian cancer cells to PaTrin-2, providing survival or apoptotic status in response to various stresses (5). an ideal therapeutic option involving the combined treatment of Ubiquitination, which is a reversible and significant post- HDACis and PaTrin-2 in ovarian cancer. translational modification responsible for regulating the stability and activity of modified proteins, is involved in the regulation of Author contributions: X.W., Q.L., and Z.L. designed research; Y.W., T.S., and B.L. collected nearly all biological process and is associated with tumorigenesis patient samples; X.W., Q.L., P.Z., W.C., and F.D. performed research; X.W., Q.L., P.Z., W.C., and development (6). In contrast, deubiquitinating enzymes (DUBs) Y.W., T.S., and B.L. analyzed data; and X.W., Q.L., and Z.L. wrote the paper. can cleave ubiquitin from substrate proteins, edit ubiquitin chains, The authors declare no conflict of interest. and process ubiquitin precursors to counterbalance the ubiquitina- This article is a PNAS Direct Submission. β tion process (7). To date, six E3s (Mule, SCF -TRCP,SCFFBW7,APC/ Published under the PNAS license. CDC20 C , Trim17, and FBXO4) have been found to be involved in 1X.W. and Q.L. contributed equally to this work. the ubiquitination process of MCL1 in proteasomal degradation (8, 2To whom correspondence should be addressed. Email: [email protected]. 9).Inaddition,USP9XandUSP13havebeenreportedtodeubi- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. quitinate MCL1 for stabilization (10, 11). However, USP9X exhibits 1073/pnas.1814742116/-/DCSupplemental. tissue-specific expression primarily in the brain and immune system Published online February 4, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1814742116 PNAS | February 19, 2019 | vol. 116 | no. 8 | 2961–2966 Downloaded by guest on September 26, 2021 Results DUB3 in the OVCAR3, OVCA433, or SKOV3 cells using short Identification of DUB3 as a Deubiquitinase Stabilizing MCL1. To sys- hairpin RNAs (shRNAs) resulted in the down-regulation of the tematically identify potential DUBs responsible for MCL1 sta- MCL1 protein but had no effect on the MCL1 mRNA levels (SI Appendix G–I bilization, we performed an unbiased screening by individually , Fig. S1 ). The cycloheximide pulse-chase assay also transfecting 66 DUBs into 293T cells and detecting the endoge- showed accelerated MCL1 degradation in ovarian cancer cells SI Appendix J–L nous MCL1 protein expression. Among the tested genes from the after the DUB3 depletion ( ,Fig.S1 ). DUB plasmid library, DUB3 emerged as the DUB with the strongest up-regulation of MCL1 (Fig. 1A and SI Appendix,Fig. DUB3 Interacts with and De-Polyubiquitinates MCL1. To investigate S1A). The ectopic expression of DUB3, but not its catalytically the DUB3-mediated regulation of MCL1, we first performed a coimmunoprecipitation (co-IP) analysis. V5-DUB3 and Flag- inactive C89S mutant (catalytic Cys89 is replaced by Ser, MCL1 were coexpressed in 293T cells, and after IP with anti-V5- DUB3C89S), resulted in an elevation in the endogenous MCL1 tag pAb-agaroses, we detected MCL1, and vice versa (Fig. 2 A protein but not mRNA expression level in a dose-dependent and B). To explore whether DUB3 selectively targets MCL1, manner (Fig. 1 B and C). Consistently, the cycloheximide pulse- immunoprecipitation was performed in Flag-DUB3-overexpressed chase assay showed that DUB3 overexpression could significantly 293T cells after both mass spectrometry and immunoblotting. The prolong the half-life of endogenous MCL1 (SI Appendix,Fig.S1B C results demonstrated that only MCL1 was strongly associated with and ). Although USP9X and USP13 also stabilize the MCL1 DUB3, whereas no other BCL-2 family member was detected (SI protein, their effects are slightly weaker than that of DUB3 (SI Appendix A B Appendix B C ,Fig.S2 and and Table S1). Consistently, DUB3 ,Fig.S1 and ). To further validate the stabilizing overexpression specifically up-regulated the expression of MCL1, but effect of the three DUBs on MCL1 in ovarian cancer, we detected not that of other BCL-2 family members in 3AO cells
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