EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

Xinyu Yang; Fengjiao Han; Xiang Hu; Guosheng Li; Hanyang Wu; Can Can; Yihong Wei; Jinting Liu; Ruiqing Wang; Wenbo Jia; Chunyan Ji; Daoxin Ma

doi:10.1186/s40364-023-00495-4

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

Biomark Res. 2023 Jun 6;11(1):59. doi: 10.1186/s40364-023-00495-4.

Authors

Xinyu Yang^#^{1

2}, Fengjiao Han^#^{1

2}, Xiang Hu^{1

2}, Guosheng Li^{1

2}, Hanyang Wu^{1

2}, Can Can^{1

2}, Yihong Wei^{1

2}, Jinting Liu^{1

2}, Ruiqing Wang^{1

2}, Wenbo Jia^{1

2}, Chunyan Ji^{1

2}, Daoxin Ma^{3

4}

Affiliations

¹ Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China.
² Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
³ Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China. daoxinma@sdu.edu.cn.
⁴ Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China. daoxinma@sdu.edu.cn.

^# Contributed equally.

Abstract

Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML); however, its regulatory mechanism remains unclear. Herein, we identified a novel circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contributes to a poor prognosis. We further validated their expression in large-scale samples and found that only the expression of Circ_0001187 was significantly decreased in newly diagnosed (ND) AML patients and increased in patients with hematological complete remission (HCR) compared with controls. Knockdown of Circ_0001187 significantly promoted proliferation and inhibited apoptosis of AML cells in vitro and in vivo, whereas overexpression of Circ _0001187 exerted the opposite effects. Interestingly, we found that Circ_0001187 decreases mRNA m⁶A modification in AML cells by enhancing METTL3 protein degradation. Mechanistically, Circ_0001187 sponges miR-499a-5p to enhance the expression of E3 ubiquitin ligase RNF113A, which mediates METTL3 ubiquitin/proteasome-dependent degradation via K48-linked polyubiquitin chains. Moreover, we found that the low expression of Circ _0001187 is regulated by promoter DNA methylation and histone acetylation. Collectively, our findings highlight the potential clinical implications of Circ _0001187 as a key tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 pathway.

Keywords: Acute myeloid leukemia; Circ_0001187; METTL3; Progression; RNF113A; miR-499a-5p.