ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

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Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR.
This work was supported by La Ligue Contre le Cancer, INCa, Canceropole PACA and INSERM to JI; Fondation ARC to PS. La Ligue Contre le Cancer (Equipe Labellisée) to VG and JI; Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017) to OA; Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III and European Union (ERDF/ESF, ‘Investing in your future’) (PI15/00663 and PI18/00343) to OA; Spanish Ministry of Economy and Competitiveness (BFU2016-78232-P to AVC, RTI2018-097991-BI00 to JLN); Diputación General de Aragón (Protein Targets and Bioactive Compounds Group E45_17R to AVC, and Digestive Pathology Group B25_17R to OA); Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd); Fondation de France to PSC; China Scholarship Council to WL and CH; Programme XU GUANGQI to YX and JI; and National Natural Science Foundation of China (81502920), the Fundamental Research Funds for the Central Universities (106112017CDJQJ468823) to YX. Part of this work was performed using the France-BioImaging infrastructure supported by the Agence Nationale de la Recherche (ANR-10-INBS-04-01, call “Investissements d’Avenir”).