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

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

  • J Biol Chem. 2023 Jan 31;102971. doi: 10.1016/j.jbc.2023.102971.
Hao Zhang 1,  Wenjun Song 2,  Xinying Ma 2,  Mingxiao Yu 2,  Lulu Chen 1,  Yanling Tao 3
Affiliations

Affiliations

  • 1 Department of Hematology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China; Institute of Blood and Marrow Transplantation, Jining Medical University, Jining, Shandong Province, China.
  • 2 Graduate School, Department of Clinical Medicine, Jining Medical University, Jining 272000, Shandong Province, China; Institute of Blood and Marrow Transplantation, Jining Medical University, Jining, Shandong Province, China.
  • 3 Department of Pediatric Hematology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China. Electronic address: taoyanling@mail.jnmc.edu.cn.
PMID: 36736423 DOI: 10.1016/j.jbc.2023.102971
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 mesenchymal stem cells (BMMCs) 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 anti-leukemic effects in an in vivo model of AML. Our mechanistic investigation demonstrated that WISP2 deacetylation was regulated by the deacetylase HDAC3. 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.

Keywords

HDAC3; NEDD4; WISP2; acetylation; leukemia; ubiquitination.

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