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FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-Cell Lymphoma Cells

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FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-Cell Lymphoma Cells Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. FBXW7 triggers degradation of KMT2D to favor growth of diffuse large B-cell lymphoma cells. 1* 1* 2 2 3 Rizwan Saffie , Nan Zhou , Delphine Rolland , Özlem Önder , Venkatesha Basrur , Sydney Campbell1, Kathryn E. Wellen1, Kojo S.J. Elenitoba-Johnson2, Brian C. Capell4,5, and Luca 1# Busino Running Title: KMT2D degradation favors B- cell growth 1 Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, phone: (215) 746-2569, [email protected] 2 Department of Pathology and Laboratory Medicine; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 3 Department of Pathology and Clinical Laboratories, University of Michigan, Ann Arbor, MI 48109 4 Penn Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA 5 Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA * These authors equally contributed. #Correspondence: Luca Busino, 421 Curie Blvd, 705 BRB II/III, Philadelphia, PA, 19104, phone: (215) 746-2569, [email protected] The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to L.B. ([email protected]). 1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. Significance Findings characterize FBXW7 as a pro-survival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D. 2 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction The ubiquitin-proteasome system (UPS) specifically promotes degradation of the majority of cellular proteins and regulates a variety of cellular processes. E3 ubiquitin ligases are the UPS effectors that recognize target proteins and promote ubiquitylation and degradation(1,2). FBXW7 (F-box/WD40 repeat-containing protein 7; gene ID: 55294) is a member of the F- box family of proteins that functions as the substrate-targeting subunit of the Skp1-Cul1-F-box ubiquitin ligase complex SCF-FBXW7(3,4). The F-box domain of FBXW7 allows interaction with Skp1, which links FBXW7 to the rest of the SCF complex(3,4). Through a C-terminal WD40 domain, FBXW7 recognizes a phosphorylated amino acid motif (or phosphodegron) in substrates(3,4). The FBXW7 phospho-degron is conserved from yeast to mammals and follows the general pattern of pS/pT-P-P-X-pS/pT/E/D (that is, a pSer or pThr, two Pro repeats, any amino acid, pSer or pThr or a phosphomimetic glutamic or aspartic acid)(3,4). Amino acid mutation of key WD40 residues or amino acid mutation of a substrate degron can ablate FBXW7-substrate interactions(5-7). FBXW7 promotes degradation of multiple substrates including CYCLIN E1, c-MYC, JUN, MCL1, and NOTCH1, several of which are known to contribute to carcinogenesis(3,4). Hence, FBXW7 is generally considered to be a tumor suppressor through its negative regulation of these oncogenic proteins. Importantly, mutations in the FBXW7 gene have been described in many solid tumors (mutation rates ranging from 4% to 30% depending on cancer type)(3,8-10). However, FBXW7 mutations are rarely observed in B-cell malignancies (11-14), suggesting a different role in this cell context. 3 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. B-cell cancers hijack the regulatory mechanisms controlling physiologic B-cell differentiation for their own advantage of growth and survival. The majority of B-cell non- Hodgkin's lymphomas (B-NHLs) (including diffuse large B-cell lymphoma (DLBCL)) and multiple myeloma (MM) are neoplastic processes derived from germinal or post-germinal center B-cells. DLBCL and MM display an elevated genetic heterogeneity that limits the efficacy of current cancer therapies(15,16). Importantly, FBXW7 was highlighted as a pro-survival factor in non-malignant B-cells: multiple myeloma, chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) (5,17-19). Thus, FBXW7 may be tumor suppressive or pro-survival in different hematologic cancer types depending on the cell context and the relevant substrate(s) targeted for proteolysis. Based on the clinical success of a proteasome inhibitor, bortezomib, as well as E3 ubiquitin ligase activators, such as the immunomodulatory imide drugs (IMiDs), the sulfonamides, and the proteolysis targeting chimeras (PROTACs)(20-23), it is critical to understand how protein ubiquitylation is achieved and what the downstream consequences of such molecular events are for the development of novel therapeutics. In this study, we focus on expanding the functional understanding of FBXW7 in B-cell cancers and propose the lysine methyl transferase 2D (KMT2D, also known as MLL2, ALR or MLL4; gene ID: 8085) as a novel substrate of FBXW7. 4 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Material and Methods Cell culture and drug treatment OPM-1, KMS-11, BJAB, SUDHL10, U2932, HLY1, and HT cells were maintained in RPMI-1640 media containing 10% fetal bovine serum (FBS). HEK293T cells were maintained in Dulbecco’s modified Eagle’s media (DMEM) containing 10% FBS. HEK293T cells were purchased from ATCC. B-cell cancer cell lines were kindly provided by Dr. Laura Pasqualucci, Dr. Michele Pagano and Dr. Yibin Yang. Cell line authentication was not performed as cells were not listed in the commonly misidentified category. All cell lines were free of mycoplasma contamination (MycoAlert kit, Lonza). Cell lines were passaged for less than 6 months after receipt or resuscitation. The following drugs were used: MG132 (Peptides International, #IZL-3175-v; 10 "M final concentration), MLN4924 (EMD Millipore, #505477; 5 µM final concentration), cycloheximide (Sigma-Aldrich, #C7698; 20 mg/mL final concentration), Doxycycline hyclate (Sigma-Aldrich, #D9891; 1 ng/mL or 1 mg/mL final concentration), and IACS-010759 (Selleck Chemicals, #S8731), puromycin (Sigma-Aldrich, 0.5–1!"g/ml final concentration), hygromycin B (EMD Millipore, #400052, 100-200 µg/mL), zeocin (100-250 µg/mL), and blasticidin S HCl (Gibco, #R21001, 3-15 µg/mL). CRISPR-derived HEK293T FBXW7–/– clones were selected using single cell cloning in 96-well plates. Cell proliferation assay and generation of drug response curve Cells were cultured in 24-well plates with 1 mL of medium and plated at equal densities on Day 0; cell numbers were counted every 3 days. After each counting, cells were re-plated at the same dilutions in 1 mL until the experimental endpoint. To assess cellular sensitivity to IACS- 010759, cells were plated at equal densities for 4 days at the indicated doses of IACS-010759. Cell counting and viability were assessed with the Attune NxT flow cytometer (Thermo Scientific). 5 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 29, 2020; DOI: 10.1158/0008-5472.CAN-19-2247 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Reagents The following antibodies were used: FLAG (Sigma, #F7425), KMT2D (Bethyl Laboratories, #A300-BL1185), UTX (Bethyl Laboratories, #A302-374A), ASH2L (Bethyl Laboratories, #A300- 489A), WDR5 (Bethyl Laboratories, #A302-430A), DPY30 (Bethyl Laboratories, #A304-296A), NCOA6 (Bethyl Laboratories, #A300-411A), CUL1 (Invitrogen,
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