Chidamide induces cell cycle arrest via NR4A3/P21 axis upregulation to suppress relapsed and refractory acute myeloid leukemia

  • Biochem Biophys Res Commun. 2024 Aug 5:737:150493. doi: 10.1016/j.bbrc.2024.150493.
Xuefeng Feng  1 ,  Fuyi Luo  2 ,  Shuyu Wang  2 ,  Feng Zhu  3 ,  Yifan Gao  1 ,  Jianmin Luo  4 ,  Jiazi Zhou  5
Affiliations
  • 1. Department of Hematology, Key Laboratory of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
  • 2. Department of Graduate School, Hebei North University, 075000, Zhangjiakou, Hebei, China.
  • 3. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 4. Department of Hematology, Key Laboratory of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. Electronic address: [email protected].
  • 5. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: [email protected].
PMID: 39133986 DOI: 10.1016/j.bbrc.2024.150493
Abstract

(1) Currently, the survival prognosis for patients with relapsed and refractory acute myeloid leukemia (R/R AML) is extremely poor. Therefore, the exploration of novel drugs is imperative to enhance the prognosis of patients with R/R AML. The therapeutic efficacy and mechanism of Chidamide, a novel epigenetic regulatory drug, in the treatment of R/R AML remain unclear.

Methods: The mechanism of action of Chidamide has been explored in various AML cell lines through various methods such as cell Apoptosis, cell cycle analysis, high-throughput transcriptome Sequencing, gene silencing, and xenograft models.

Results: Here, we have discovered that chidamide potently induces Apoptosis, G0/G1 phase arrest, and mitochondrial membrane potential depolarization in R/R AML cells, encompassing both primary cells and cell lines. Through RNA-seq analysis, we further revealed that chidamide epigenetically regulates the upregulation of differentiation-related pathways while suppressing those associated with cell replication and cell cycle progression. Notably, our screening identified NR4A3 as a key suppressor gene whose upregulation by chidamide leads to P21-dependent cell cycle arrest in the G0/G1 phase.

Conclusions: We have discovered a novel epigenetic regulatory mechanism of chidamide in the treatment of relapsed and refractory acute myeloid leukemia (R/R AML).

Keywords
Acute myeloid leukemia; Cell cycle; Epigenetic regulation; NR4A3; P21; Prognostic.
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