c-Myc suppresses miR-451⊣YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia
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Rui Su1, Jia-Nan Gong1, Ming-Tai Chen1, Li Song1, Chao Shen1, Xin-Hua Zhang2, Xiao-Lin Yin2, Hong-Mei Ning3, Bing Liu4, Fang Wang1, Yan-Ni Ma1, Hua-Lu Zhao1, Jia Yu1, Jun-Wu Zhang1
1The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2Department of Hematology, The 303 Hospital, Nanning, Guangxi, China
3Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to Academy of Military Medical Sciences, The 307 Hospital, Beijing, China
4State Key Laboratory of Proteomics, Translational Medicine Center of Stem Cells, 307-lvy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
Jun-Wu Zhang, email: firstname.lastname@example.org
Keywords: acute myeloid leukemia, microRNA-451, c-Myc, HDAC3, YWHAZ
Received: February 20, 2016 Accepted: September 20, 2016 Published: October 15, 2016
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.
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