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Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma

ABSTRACT: Relapsed/refractory multiple myeloma (r/r MM) is a disease with often poor prognosis. Hyperactive SUMO signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. Here, we found that r/r MM is characterized by a SUMO-high state, and high expression of SUMO E1 ligase (SAE1/UBA2) was associated with poor overall survival. Induced resistance to the second generation proteasome inhibitor (PI) carfilzomib (CFZ) enhanced SUMO pathway activity. Accordingly, CFZ-pretreated patients showed enhanced SUMO pathway activity in the MM compartment. Treatment of MM cell lines with subasumstat, a novel small-molecule SUMO E1 activating enzyme inhibitor, showed synergistic treatment efficacy with CFZ in both PI-sensitive and PI-resistant MM cell lines irrespective of the TP53 state. Combination therapy was effective in two murine MM xenograft models, where in vivo growth was significantly inhibited, and in patient-derived primary MM cells in vitro. Mechanistically, combined subasumstat and CFZ treatment enhanced DNA stress and apoptosis. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel potent strategy for the treatment of patients with MM.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Multiple Myeloma Cell Line, Cell Line Cell

DISEASE(S): Multiple Myeloma

SUBMITTER: Evelyn Ramberger

LAB HEAD: Philipp Mertins

PROVIDER: PXD032316 | Pride | 2022-08-01

REPOSITORIES: Pride

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Project description:The essential process of dosage compensation equalizes X-chromosome gene expression between C. elegans XO males and XX hermaphrodites through a dosage compensation complex (DCC) that resembles condensin. The DCC binds to both X chromosomes of hermaphrodites to repress transcription by half. Here we show that post-translational modification by the SUMO conjugation pathway is essential for sex-specific assembly of the DCC onto X. Depletion of the SUMO peptide in vivo severely disrupts binding of particular DCC subunits and causes changes in X-linked gene expression similar to those caused by disrupting genes encoding DCC subunits. Three DCC subunits are themselves SUMOylated, and depletion of SUMO preferentially reduces their binding to X, suggesting that SUMOylation of DCC subunits is essential for robust association with X. DCC SUMOylation is triggered by the signal that initiates DCC assembly onto X. The initial step of assembly--binding of X-targeting factors to recruitment sites on X (rex sites)--is independent of SUMOylation, but robust binding of the complete complex requires SUMOylation. SUMOylated DCC subunits are enriched at rex sites, and SUMOylation enhances interactions between X-targeting factors and condensin subunits that facilitate DCC binding beyond the low level achieved without SUMOylation. DCC subunits also participate in condensin complexes essential for chromosome segregation, but their SUMOylation occurs only in the context of the DCC. Our results reinforce a newly emerging theme in which multiple proteins of a complex are SUMOylated in response to a specific stimulus, leading to accelerated complex formation and enhanced function. ChIP-chip experiments using antibodies against DPY-27, SDC-3, DPY-30, DPY-26, DPY-28 and FLAG-tagged SDC-2 in wild-type and smo-1 RNAi treated mixed embryos, with IGG controls. Also, sequential ChIP-chip experiments: (1) ChIP using FLAG antibodies to determine the genome-wide binding sites for SUMOylated proteins, (2) ChIP using FLAG antibodies followed by re-ChIP of eluted protein-chromatin complexes with DPY-27 antibodies to determine genome-wide binding sites for SUMOylated DPY-27 (referred to as DPY-27 re-ChIP experiments), (3) ChIP using FLAG antibodies followed by re-ChIP of eluted protein-chromatin with IGG antibodies to determine background binding (referred to as IGG re-ChIP experiments, and (4) ChIP using DPY-27 antibodies as a control to assess the efficiency of DPY-27 binding and detection in control vs. FLAG-tagged strains.

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Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma

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