{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:33:19Z","timestamp":1789014799333,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Associazione Italiana per la Ricerca sul Cancro (AIRC)","award":["21585"],"award-info":[{"award-number":["21585"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro (AIRC)","award":["IG24365"],"award-info":[{"award-number":["IG24365"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro (AIRC)","award":["RILO 2020-2022"],"award-info":[{"award-number":["RILO 2020-2022"]}]},{"name":"University of Torino","award":["21585"],"award-info":[{"award-number":["21585"]}]},{"name":"University of Torino","award":["IG24365"],"award-info":[{"award-number":["IG24365"]}]},{"name":"University of Torino","award":["RILO 2020-2022"],"award-info":[{"award-number":["RILO 2020-2022"]}]},{"name":"Italian Ministry of Health","award":["21585"],"award-info":[{"award-number":["21585"]}]},{"name":"Italian Ministry of Health","award":["IG24365"],"award-info":[{"award-number":["IG24365"]}]},{"name":"Italian Ministry of Health","award":["RILO 2020-2022"],"award-info":[{"award-number":["RILO 2020-2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ\/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients.<\/jats:p>","DOI":"10.3390\/cancers15082199","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:19:54Z","timestamp":1681096794000},"page":"2199","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines"],"prefix":"10.3390","volume":"15","author":[{"given":"Elisabetta","family":"Mereu","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Abbo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2306-8932","authenticated-orcid":false,"given":"Tina","family":"Paradzik","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Department of Physical Chemistry, Rudjer Boskovic Insitute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Cumerlato","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Bandini","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-7235","authenticated-orcid":false,"given":"Maria","family":"Labrador","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Maccagno","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-3445","authenticated-orcid":false,"given":"Domenica","family":"Ronchetti","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-7283","authenticated-orcid":false,"given":"Veronica","family":"Manicardi","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Neri","sequence":"additional","affiliation":[{"name":"Scientific Directorate, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-3470","authenticated-orcid":false,"given":"Roberto","family":"Piva","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Medical Genetics Unit, Citt\u00e0 della Salute e della Scienza University Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"Pawlyn","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat. 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