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Distinct nuclear localization signals confer differential microtubule dependence among ZFTA fusion oncoproteins.

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Τίτλος: Distinct nuclear localization signals confer differential microtubule dependence among ZFTA fusion oncoproteins.
Συγγραφείς: Ishii M; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan. Electronic address: m_ishii@musashino-u.ac.jp., Suto N; Drug Discovery Initiative (DDI), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan., Kojima R; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan., Katakawa K; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan; Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Yokohama, Kanagawa, Japan., Makino K; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan., Toma-Fukai S; Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Nara, Japan., Tsusaka T; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan., Sueki S; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan., Anada M; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan., Kojima H; Drug Discovery Initiative (DDI), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan., Ohata S; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan. Electronic address: shiohata@musashino-u.ac.jp.
Πηγή: The Journal of biological chemistry [J Biol Chem] 2026 Sep; Vol. 302 (9), pp. 113320. Date of Electronic Publication: 2026 Jul 13.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Imprint Name(s): Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
Ιατρικοί όροι (MeSH): Microtubules*/metabolism , Oncogene Proteins, Fusion*/metabolism , Oncogene Proteins, Fusion*/genetics , Oncogene Proteins, Fusion*/chemistry , Nuclear Localization Signals*/metabolism, Colchicine/pharmacology ; Colchicine/chemistry ; Tubulin Modulators/pharmacology ; Humans ; Animals
Περίληψη: Ependymomas are glial tumors that exhibit high resistance to chemotherapy. ZFTA-fusion-positive supratentorial ependymoma (ST-EPN-ZFTA) represents a subclass with a poor prognosis. ST-EPN-ZFTA expresses fusion proteins, which consist of zinc finger translocation-associated (ZFTA) combined with a transcriptional regulator, predominantly RELA. Unlike wild-type RELA, which translocates to the nucleus in a stimulus-dependent manner, ZFTA-RELA constitutively localizes to the nucleus and induces oncogenic gene expression. To identify inhibitors of this aberrant gene expression, 9600 structurally diverse compounds were screened using a ZFTA-RELA-responsive luciferase reporter system. The screen identified a colchicine derivative, and subsequent evaluation revealed colchicine, a microtubule polymerization inhibitor, as the most potent inhibitor (IC50 of 90 nM). Colchicine attenuated ZFTA-RELA-upregulated endogenous genes, including L1CAM. Colchicine and another microtubule polymerization inhibitor, vinblastine, partially inhibited ZFTA-RELA nuclear localization, similar to the dynein motor protein inhibitors, ciliobrevin D and dynarrestin. This inhibition was mediated through the RELA region of ZFTA-RELA, indicating that RELA retains its microtubule-dependent nuclear import machinery, even in a fusion scenario. Among other ZFTA-fusion proteins, colchicine reduced nuclear localization of ZFTA-NCOA2 and ZFTA-MKL2, but not ZFTA-MAML2 and ZFTA-MAML3. In these fusion proteins, we identified three candidate nuclear localization signals (NLS) exhibiting colchicine-sensitive nuclear localization activity, two within the ZFTA regions absent in ZFTA-RELA and one within MKL2. The results indicate that the microtubule dependence of nuclear localization varies among different ZFTA-fusion partners, which may be attributable to unique NLS sequences in each fusion protein. Our results suggest that microtubule-dependent nuclear transport represents a therapeutic target in ZFTA-fusion-positive tumors.
(Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
Contributed Indexing: Keywords: ZFTA; colchicine; dynein; ependymoma; microtubule; nuclear localization
Substance Nomenclature: 0 (Oncogene Proteins, Fusion)
0 (Nuclear Localization Signals)
SML2Y3J35T (Colchicine)
0 (Tubulin Modulators)
Entry Date(s): Date Created: 20260713 Date Completed: 20260922 Latest Revision: 20260922
Update Code: 20260923
PubMed Central ID: PMC13474238
DOI: 10.1016/j.jbc.2026.113320
PMID: 42442495
Βάση Δεδομένων: MEDLINE
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  Data: Distinct nuclear localization signals confer differential microtubule dependence among ZFTA fusion oncoproteins.
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  Data: <searchLink fieldCode="AU" term="%22Ishii+M%22">Ishii M</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan. Electronic address: m_ishii@musashino-u.ac.jp.<br /><searchLink fieldCode="AU" term="%22Suto+N%22">Suto N</searchLink>; Drug Discovery Initiative (DDI), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Kojima+R%22">Kojima R</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Katakawa+K%22">Katakawa K</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan; Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Yokohama, Kanagawa, Japan.<br /><searchLink fieldCode="AU" term="%22Makino+K%22">Makino K</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Toma-Fukai+S%22">Toma-Fukai S</searchLink>; Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Nara, Japan.<br /><searchLink fieldCode="AU" term="%22Tsusaka+T%22">Tsusaka T</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Sueki+S%22">Sueki S</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Anada+M%22">Anada M</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Kojima+H%22">Kojima H</searchLink>; Drug Discovery Initiative (DDI), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan.<br /><searchLink fieldCode="AU" term="%22Ohata+S%22">Ohata S</searchLink>; Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo, Japan. Electronic address: shiohata@musashino-u.ac.jp.
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  Data: Ependymomas are glial tumors that exhibit high resistance to chemotherapy. ZFTA-fusion-positive supratentorial ependymoma (ST-EPN-ZFTA) represents a subclass with a poor prognosis. ST-EPN-ZFTA expresses fusion proteins, which consist of zinc finger translocation-associated (ZFTA) combined with a transcriptional regulator, predominantly RELA. Unlike wild-type RELA, which translocates to the nucleus in a stimulus-dependent manner, ZFTA-RELA constitutively localizes to the nucleus and induces oncogenic gene expression. To identify inhibitors of this aberrant gene expression, 9600 structurally diverse compounds were screened using a ZFTA-RELA-responsive luciferase reporter system. The screen identified a colchicine derivative, and subsequent evaluation revealed colchicine, a microtubule polymerization inhibitor, as the most potent inhibitor (IC<subscript>50</subscript> of 90 nM). Colchicine attenuated ZFTA-RELA-upregulated endogenous genes, including L1CAM. Colchicine and another microtubule polymerization inhibitor, vinblastine, partially inhibited ZFTA-RELA nuclear localization, similar to the dynein motor protein inhibitors, ciliobrevin D and dynarrestin. This inhibition was mediated through the RELA region of ZFTA-RELA, indicating that RELA retains its microtubule-dependent nuclear import machinery, even in a fusion scenario. Among other ZFTA-fusion proteins, colchicine reduced nuclear localization of ZFTA-NCOA2 and ZFTA-MKL2, but not ZFTA-MAML2 and ZFTA-MAML3. In these fusion proteins, we identified three candidate nuclear localization signals (NLS) exhibiting colchicine-sensitive nuclear localization activity, two within the ZFTA regions absent in ZFTA-RELA and one within MKL2. The results indicate that the microtubule dependence of nuclear localization varies among different ZFTA-fusion partners, which may be attributable to unique NLS sequences in each fusion protein. Our results suggest that microtubule-dependent nuclear transport represents a therapeutic target in ZFTA-fusion-positive tumors.<br /> (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.)
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