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RUVBL1 and RUVBL2 form a subcomplex of many chromatin remodeling complexes implicated in cancer progression. As an inhibitor specific to the RUVBL1\/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt\u2019s lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility. CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4\/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis.<\/jats:p>","DOI":"10.3390\/ijms25169022","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T09:13:48Z","timestamp":1724145228000},"page":"9022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Signatures of CB-6644 Inhibition of the RUVBL1\/2 Complex in Multiple Myeloma"],"prefix":"10.3390","volume":"25","author":[{"given":"Weijun","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"},{"name":"Lane Department of Computer Science & Electrical Engineering, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian A.","family":"Dziadowicz","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4592-2047","authenticated-orcid":false,"given":"Rachel S.","family":"Mangano","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"},{"name":"Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"McBee","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven M.","family":"Frisch","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-4084","authenticated-orcid":false,"given":"Lori A.","family":"Hazlehurst","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morganton, WV 26506, USA"},{"name":"WVU Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald A.","family":"Adjeroh","sequence":"additional","affiliation":[{"name":"Lane Department of Computer Science & Electrical Engineering, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-6888","authenticated-orcid":false,"given":"Gangqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA"},{"name":"WVU Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jmb.2006.11.030","article-title":"Dodecameric structure and ATPase activity of the human TIP48\/TIP49 complex","volume":"366","author":"Puri","year":"2007","journal-title":"J. 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