Acetylation stabilizes the signaling protein WISP2 by preventing its degradation to suppress the progression of acute myeloid leukemia.

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  • Additional Information
    • Source:
      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
    • Publication Information:
      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
    • Subject Terms:
      Leukemia, Myeloid, Acute*/genetics ; CCN Intercellular Signaling Proteins*/genetics ; Repressor Proteins*/genetics; Humans ; Acetylation ; Apoptosis ; Cell Line, Tumor ; Histone Deacetylase Inhibitors/pharmacology ; Valproic Acid/pharmacology ; HL-60 Cells
    • Abstract:
      Acute myeloid leukemia (AML) is challenging to treat due to its heterogeneity, prompting a deep understanding of its pathogenesis mechanisms, diagnosis, and treatment. Here, we found reduced expression and acetylation levels of WISP2 in bone marrow mononuclear cells from AML patients and that AML patients with lower WISP2 expression tended to have reduced survival. At the functional level, overexpression of WISP2 in leukemia cells (HL-60 and Kasumi-1) suppressed cell proliferation, induced cell apoptosis, and exerted antileukemic effects in an in vivo model of AML. Our mechanistic investigation demonstrated that WISP2 deacetylation was regulated by the deacetylase histone deacetylase (HDAC)3. In addition, we determined that crosstalk between acetylation and ubiquitination was involved in the modulation of WISP2 expression in AML. Deacetylation of WISP2 decreased the stability of the WISP2 protein by boosting its ubiquitination mediated by NEDD4 and proteasomal degradation. Moreover, pan-HDAC inhibitors (valproic acid and trichostatin A) and an HDAC3-specific inhibitor (RGFP966) induced WISP2 acetylation at lysine K6 and prevented WISP2 degradation. This regulation led to inhibition of proliferation and induction of apoptosis in AML cells. In summary, our study revealed that WISP2 contributes to tumor suppression in AML, which provided an experimental framework for WISP2 as a candidate for gene therapy of AML.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: HDAC3; NEDD4; WISP2; acetylation; leukemia; ubiquitination
    • Accession Number:
      0 (Histone Deacetylase Inhibitors)
      614OI1Z5WI (Valproic Acid)
      0 (CCN5 protein, human)
      0 (CCN Intercellular Signaling Proteins)
      0 (Repressor Proteins)
      EC 3.5.1.98 (histone deacetylase 3)
    • Publication Date:
      Date Created: 20230203 Date Completed: 20230406 Latest Revision: 20230406
    • Publication Date:
      20231215
    • Accession Number:
      PMC9996369
    • Accession Number:
      10.1016/j.jbc.2023.102971
    • Accession Number:
      36736423