Abstract
Aberrant activation of c-Myc plays an important oncogenic role via regulating a series of coding and non-coding genes in acute myeloid leukemia (AML). Histone deacetylases (HDACs) can remove acetyl group from histone and regulate gene expression via changing chromatin structure. Here, we found miR-451 is abnormally down-regulated in AML patient samples; c-Myc recruits HDAC3 to form a transcriptional suppressor complex, co-localizes on the miR-451 promoter, epigenetically inhibits its transcription and finally induces its downregulation in AML. Furthermore, our in vitro and in vivo results suggest that miR-451 functions as a tumor suppressor via promoting apoptosis and suppressing malignant cell proliferation. The mechanistic study demonstrated that miR-451 directly targets YWHAZ mRNA and suppresses YWHAZ/AKT signaling in AML. Knockdown of c-Myc results in restoration of miR-451 and inhibition of YWHAZ/AKT signaling. In AML patients, low level of miR-451 is negatively correlated with high levels of c-Myc and YWHAZ, while c-Myc level is positively related to YWHAZ expression. These results suggested that c-Myc⊣miR-451⊣YWHAZ/AKT cascade might play a crucial role during leukemogenesis, and reintroduction of miR-451 could be as a potential strategy for AML therapy.
Highlights
Acute myeloid leukemia (AML) is a heterogenous disorder of aggressive hematopoietic disease characterized by malignant proliferation of clonal neoplastic cells and differentiation arrest of myeloid blasts [1,2,3]
These results suggested that c-Myc⊣miR451⊣YWHAZ/AKT cascade might play a crucial role during leukemogenesis, and reintroduction of miR-451 could be as a potential strategy for acute myeloid leukemia (AML) therapy
Becker H. et al and Whitman SP. et al reported that miR-451 is underexpressed in AML with NPM1 mutation and FLT3-ITD mutation, and deregulation of miR-451 correlated with adverse prognosis in AML with FLT3-ITD mutation [36, 37]
Summary
Acute myeloid leukemia (AML) is a heterogenous disorder of aggressive hematopoietic disease characterized by malignant proliferation of clonal neoplastic cells and differentiation arrest of myeloid blasts [1,2,3]. In vitro and in vivo reintroduction of miR-451 could promote cell apoptosis and inhibit uncontrolled proliferation via directly targeting YWHAZ/ AKT signaling. The data indicated that forced expression of c-Myc could significantly inhibit the transcriptional activity of miR-451 promoter, while deletion of the c-Myc binding site abolished this suppression in HEK-293T cells (Figure 2D).
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