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ACUTE MYELOID LEUKEMIA

HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA

Leukemia volume 37, pages 1254–1267 (2023)Cite this article

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Abstract

Hypoxia inducible factor 1α (HIF1α) is abnormally overexpressed in t(8;21) acute myeloid leukemia (AML) and functions as an oncogene through transactivating DNA methyltransferase 3 alpha leading to DNA hypermethylation. However, it remains unclear whether HIF1α influences RNA N6-methyladenosine (m6A) methyltransferases. Here, we show that HIF1α promotes the expression of Wilms tumor 1-associated protein (WTAP), a main component of the m6A methyltransferase complex, markedly alters the transcriptome-wide m6A distribution and enhances cell proliferation in t(8;21) AML. In agreement with this, WTAP is overexpressed and predicts poor prognosis in t(8;21) AML patients. Moreover, WTAP knockdown inhibits growth, and induces apoptosis and differentiation of leukemia cells. Mechanistically, HIF1α transactivates WTAP gene expression by directly binding to the hypoxia-response element of its promoter region. Pharmacological or genetic intervention in the HIF1α-WTAP axis results in the reduction of m6A level on lysine demethylase 4B (KDM4B) transcripts and increased its degradation, correlated with lower expression of KDM4B and higher trimethylation levels of histone H3 on lysine 9. KDM4B knockdown inhibits leukemia cell growth in vitro and in mice. Thus, HIF1α-mediated WTAP high expression enhances the malignant behavior of leukemia cells and drives a crosstalk between m6A RNA methylation and histone methylation through monitoring m6A-dependant KDM4B translation.

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Fig. 1: High WTAP expression levels are positively correlates with HIF1α expression and indicate inferior prognosis in t(8;21) AML.
Fig. 2: Silencing of WTAP expression inhibits proliferation ability of t(8;21) AML cells.
Fig. 3: HIF1α promotes WTAP expression at the transcriptional level by binding directly to the WTAP promoter.
Fig. 4: HIF1α induces KDM4B gene high expression through WTAP-mediated m6A methylation modification.
Fig. 5: Silencing of WTAP decreases m6A methylation of expression levels of KDM4B.
Fig. 6: High KDM4B expression levels are positively correlates with HIF1α/WTAP expression and indicate inferior prognosis in t(8;21) AML, and silencing of KDM4B expression inhibits leukemia cell proliferation ability.
Fig. 7: HIF1α-WTAP axis catalyzes the demethylation of trimethylated Lys9 in histone H3 (H3K9me3) by inducing KDM4B expression.

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Data availability

The m6A sequencing data have been deposited in Gene Expression Omnibus (GEO) with the accession code GSE168778, GSE200605 and GSE214225.

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Funding

Funding

This work was supported by research grants from the National Natural Science Foundation of China (82070149 [XNG], 81870109 [XNG] and 82030076 [LY]) and the Natural Science Foundation of Beijing Municipality (7202191 [XNG]).

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Author notes

  1. These authors contributed equally: Yang-Liu Shao, Yu-Qing Li, Meng-Yue Li, Li-Li Wang.

  2. These authors jointly supervised this work: Ji Lin, Xiao-Ning Gao.

Authors and Affiliations

  1. Senior Department of Hematology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China

    Yang-Liu Shao, Yu-Qing Li, Meng-Yue Li, Li-Li Wang, Hui-Sheng Zhou, Dai-Hong Liu & Xiao-Ning Gao

  2. Graduate School, Chinese PLA General Hospital, Beijing, China

    Yang-Liu Shao, Yu-Qing Li, Meng-Yue Li, Hui-Sheng Zhou & Ji Lin

  3. Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen, Guangdong, China

    Li Yu

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Contributions

XNG conceived ideas and designed the experiments; YLS, YQL, MYL, LLW, and HSZ performed the experiments; LLW, LY, DHL, and JL critically reviewed the paper; YLS, YQL, and XNG carried out statistical analysis; JL and XNG interpreted data and wrote the paper. All authors vouch for the completeness and accuracy of the data and analysis.

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Correspondence to Ji Lin or Xiao-Ning Gao.

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Shao, YL., Li, YQ., Li, MY. et al. HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA. Leukemia 37, 1254–1267 (2023). https://doi.org/10.1038/s41375-023-01904-1

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