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

Hypoxia inducible factor 1 alpha (HIF1 alpha) 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 HIF1 alpha influences RNA N-6-methyladenosine (m(6)A) methyltransferases. Here, we show that HIF1 alpha promotes the expression of Wilms tumor 1-associated protein (WTAP), a main component of the m(6)A methyltransferase complex, markedly alters the transcriptome-wide m(6)A 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, HIF1 alpha transactivates WTAP gene expression by directly binding to the hypoxia-response element of its promoter region. Pharmacological or genetic intervention in the HIF1 alpha-WTAP axis results in the reduction of m(6)A 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, HIF1 alpha-mediated WTAP high expression enhances the malignant behavior of leukemia cells and drives a crosstalk between m(6)A RNA methylation and histone methylation through monitoring m(6)A-dependant KDM4B translation.