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Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair And

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Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair And Published OnlineFirst March 7, 2017; DOI: 10.1158/1078-0432.CCR-16-2692 Cancer Therapy: Preclinical Clinical Cancer Research Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells Deepika Sharma Das1, Abhishek Das2, Arghya Ray1, Yan Song1, Mehmet Kemal Samur1, Nikhil C. Munshi1, Dharminder Chauhan1, and Kenneth C. Anderson1 Abstract Purpose: The ubiquitin proteasome pathway is a validated tiple myeloma cell growth, and overcomes bortezomib resistance. therapeutic target in multiple myeloma. Deubiquitylating SJB triggers apoptosis in multiple myeloma cells via activation of enzyme USP1 participates in DNA damage response and cellular caspase-3, caspase-8, and caspase-9. Moreover, SJB degrades USP1 differentiation pathways. To date, the role of USP1 in multiple and downstream inhibitor of DNA-binding proteins as well as myeloma biology is not defined. In the present study, we inves- inhibits DNA repair via blockade of Fanconi anemia pathway and tigated the functional significance of USP1 in multiple myeloma homologous recombination. SJB also downregulates multiple using genetic and biochemical approaches. myeloma stem cell renewal/survival-associated proteins Notch-1, Experimental Design: To investigate the role of USP1 in Notch-2, SOX-4, and SOX-2. Moreover, SJB induced generation of myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies more mature and differentiated plasma cells. Combination of SJB in myeloma cell lines and patient multiple myeloma cells. and HDACi ACY-1215, bortezomib, lenalidomide, or pomalido- Results: USP1-siRNA knockdown decreases multiple myeloma mide triggers synergistic cytotoxicity. cell viability. USP1 inhibitor SJB selectively blocks USP1 enzy- Conclusions: Our preclinical studies provide the framework matic activity without blocking other DUBs. SJB also decreases the for clinical evaluation of USP1 inhibitors, alone or in combina- viability of multiple myeloma cell lines and patient tumor cells, tion, as a potential novel multiple myeloma therapy. Clin Cancer inhibits bone marrow plasmacytoid dendritic cell–induced mul- Res; 1–10. Ó2017 AACR. Introduction maintain cellular protein homeostasis by modulating protein activation, turnover rate, recycling, and localization (4). Alter- Proteasome inhibitors are effective therapy for relapsed/ ation in DUBs activity has been linked with several diseases, refractory, relapsed, and newly diagnosed multiple myeloma; including cancer (5, 6). The human genome encodes about however, the development of resistance and relapse of di- 100 DUBs, which are classified into 5 families: the USP (the sease is common (1–3). Recent research discovered novel drugs ubiquitin-specific processing protease), UCH (the ubiquitin that modulate protein ubiquitin-conjugating/deconjugating C-terminal hydrolase), OTU (the ovarian tumor), MJD (the enzymes rather than the proteasome itself. We recently showed Josephin domain), and JAMM (the Jab1/Mov34 metalloenzyme). that targeting deubiquitylating enzymes (DUBs) USP14, The first 4 families are cysteine proteases, whereas the fifth family UCHL5, and USP7 can overcome proteasome inhibitor resis- is metalloproteases, and to date, USP and UCH are the best tance in multiple myeloma (4–8). characterized families (4). DUBs deconjugate ubiquitin from targeted proteins and facil- USP1 regulates DNA repair through Fanconi anemia (FA) itate regeneration of free ubiquitin pools (4). In addition, DUBs pathway by deubiquitylating DNA repair proteins, FANCD2-Ub and PCNA-Ub (9). For example, USP1 deubiquitylates mono- 1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, ubiquitylated PCNA, which inhibits recruitment of DNA poly- Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. merases in the absence of DNA damage, and thereby leads to 2Program in Cellular and Molecular Medicine, Children's Hospital, Boston, Massachusetts. regulated DNA repair. USP1 also regulates DNA break repair via homologous recombination (HR) pathway (10). Conversely, Note: Supplementary data for this article are available at Clinical Cancer inhibition of USP1 sensitizes cancer cells to chemotherapy and Research Online (http://clincancerres.aacrjournals.org/). radiation (9). As USP1 participates in DNA damage response D. Chauhan and K.C. Anderson are joint senior authors. pathways, USP1-knockout mice are genetically unstable and Corresponding Authors: Dharminder Chauhan, M-557, Mayer Building, Dana highly sensitive to DNA damage (11). Finally, USP1 inhibits cell Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail: differentiation by stabilizing tumor-promoting inhibitor of [email protected]; and Kenneth C. Anderson, DNA-binding (ID) proteins (12, 13). To date, the role of USP1 [email protected] in multiple myeloma biology is undefined. In the present study, doi: 10.1158/1078-0432.CCR-16-2692 we investigated the functional significance of USP1 in multiple Ó2017 American Association for Cancer Research. myeloma using genetic and biochemical approaches. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst March 7, 2017; DOI: 10.1158/1078-0432.CCR-16-2692 Das et al. Ubiquitin vinyl sulfone labeling, Ub-AMC, and tetraubiquitin Translational Relevance chain cleavage assays Proteasome inhibitors are effective therapy for multiple Cells were treated with or without SJB for 3 hours and were myeloma; however, the development of resistance and harvested and lysed. Total protein (25 mg) was labeled with relapse of disease are common. Recent research discovered hemaglutinnin (HA)-linked Ub-VS probe (1 mmol/L) for 30 novel drugs that modulate protein ubiquitin-conjugating/ minutes at 37C and analyzed with immunoblotting. deconjugating enzymes rather than the proteasome itself, thus leading to less toxic side effects, and can overcome Ub-AMC assay proteasome inhibitor resistance in multiple myeloma. In recombinant DUBs (rDUB; USP1/UAF1, USP2, USP5, USP7, or this study, we show that USP1 inhibition by SJB3-019A UCH37) were incubated with SJB for 30 minutes at 37C, and decreases cell viability in multiple myeloma cells. The mod- then UB-AMC was added for another 30 minutes, followed by ulation of ID proteins and DNA repair proteins by USP1 measurement of fluorescence intensity. inhibitor SJB3-019A shown here has further biologic impli- cations and clinical applications. SJB3-019A–mediated inhi- Ubiquitin-linked K48 chain cleavage assay bition of USP1/ID/Notch/Sox2 pathway triggers immature Purified rDUBs were incubated with SJB for 30 minutes, fol- plasma cells to differentiate, mature, and undergo apoptosis. lowed by the addition of K48-linked tetraubiquitin chains. The Isobologram analysis demonstrated that the combination of reaction was terminated after 30 minutes by addition of reducing SJB3-019A with bortezomib, HDAC6i ACY1215, lenalido- buffer, and samples were analyzed by Western blotting (17). mide, or pomalidomide triggers synergistic anti–multiple myeloma activity. Our preclinical data support clinical inves- Immunostaining tigation of USP1 inhibitors alone or in combination with Multiple myeloma cells were stained with Rad51 Ab and other agents in multiple myeloma. Giemsa stain as described previously, and sections were then imaged by microscopy (18). USP1 gene expression analysis Materials and Methods The exon-1.0 ST array data for 170 newly diagnosed patients with multiple myeloma were quality-controlled and normalized Cell culture and reagents with aroma Affymetrix package. Gene expression was estimated Multiple myeloma cell lines and normal donor–derived with a PLM model. The survival analysis was carried out using the peripheral blood mononuclear cells (PBMC) were cultured R package. in complete medium containing 10% FBS and antibiotics. All cell lines were tested for mycoplasma contamination using Survival MycoAlertTM mycoplasma detection kit (Lonza). Plasmacytoid The raw data for expression profiling and the CEL files can be dendritic cells (pDC), bone marrow stromal cells (BMSC), or found at the website Gene Expression Omnibus (http://www. tumor cells from patients with multiple myeloma were purified ncbi.nlm.nih.gov/geo/) under accession numbers: GSE5900 and and cultured as described previously (14). All patient samples GSE2658. Survival data can be accessed at https://www.ncbi.nlm. were obtained with prior informed consent in accordance nih.gov/geo/query/acc.cgi?acc¼GSE39754. Helsinki protocol. Bone marrow mononuclear cells (MNC) were purchased from Allcells (USA). SJB3-019A (SJB), borte- Statistical analysis zomib, lenalidomide, pomalidomide, and ACY-1215 were The Student t test was utilized to derive statistical signifi- obtained from Selleck chemicals (USA). cance. Synergistic cytotoxic activity of combination regimes was assessed with isobologram analysis and CalcuSyn software Cell cycle, cell viability, and apoptosis assays program (19). Cell-cycle analysis was performed as described previously (15). Cell viability was assessed by WST-1/CellTiter-Glo (CTG) Lumi- nescent assays, as in prior study (16). Apoptosis was measured by Results Annexin/propidium iodide (PI) staining. USP1 expression analysis in multiple myeloma cells Examination of gene expression datasets showed a higher USP1 Western blotting assays in clonal plasma cells from patients with monoclonal gammo- Immunoblotting was performed as previously
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