Transmembrane Protein ANTXR1 Regulates γ-Globin Expression by Targeting the Wnt/β-Catenin Signaling Pathway

• Published in: Journal of Immunology Research Vol. 2022; pp. 1 - 17
• Main Authors: Jin, Tingting, Zhang, Zhaojun, Han, Yuanyuan, Li, Di, Liu, Juan, Jiang, Minmin, Zhu, Junwei, Kurita, Ryo, Nakamura, Yukio, Hu, Fangfang, Xu, Yongjie, Fang, Xiangdong, Huang, Shengwen, Sun, Zhaolin
• Format: Journal Article
• Language: English
• Published: New York Hindawi 30.07.2022; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Anthrax; Antibodies; Blood diseases; c-Jun protein; CD34 antigen; Cord blood; Ethylenediaminetetraacetic acid; Fetuses; Gene expression; Gene silencing; Genes; Genetic transcription; Hematology; Hemoglobin; Immunology; Lithium chloride; Mutation; Peripheral blood; Plasmids; Proteins; Sickle cell anemia; Sickle cell disease; Signal transduction; Sox6 protein; Thalassemia; Transcription factors; Transmembrane proteins; Vectors (Biology); Wnt protein; β-Catenin; China; Beijing China
• ISSN: 2314-8861; 2314-7156
• DOI: 10.1155/2022/8440422

Reactivation of fetal hemoglobin (HbF, α2γ2) alleviates clinical symptoms in patients with β-thalassemia and sickle cell disease, although the regulatory mechanisms of γ-globin expression have not yet been fully elucidated. Recent studies found that interfering with the expression of the membrane protein ANTXR1 gene upregulated γ-globin levels. However, the exact mechanism by which ANTXR1 regulates γ-globin levels remains unclear. Our study showed that overexpression and knockdown of ANTXR1 in K562, cord blood CD34+, and HUDEP-2 cells decreased and increased γ-globin expression, respectively. ANTXR1 regulates the reactivation of fetal hemoglobin (HbF, α2γ2) in K562, cord blood CD34+, and adult peripheral blood CD34+ cells through interaction with LRP6 to promote the nuclear entry of β-catenin and activate the Wnt/β-catenin signaling pathway. The overexpression or knockdown of ANTXR1 on γ-globin and Wnt/β-catenin signaling in K562 cells was reversed by the inhibitor XAV939 and the activator LiCl, respectively, where XAV939 inhibits the transcription of β-catenin in the Wnt pathway, but LiCl inhibits GSK3-β. We also showed that the binding ability of the rank4 site in the transcriptional regulatory region of the SOX6 gene to c-Jun was significantly increased after overexpression of ANTXR1 in K562 cells. SOX6 protein expression was increased significantly after overexpression of the c-Jun gene, indicating that the transcription factor c-Jun initiated the transcription of SOX6, thereby silencing γ-globin. Our findings may provide a new intervention target for the treatment of β-hemoglobinopathies.