title: c-Myc suppresses miR-451⊣YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia.
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.
authors.affiliation: The 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: The 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.
authors.forename: Jia-Nan
authors.initials: JN
authors.lastname: Gong
authors.affiliation: The 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.
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Chen
authors.affiliation: The 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.
authors.forename: Li
authors.initials: L
authors.lastname: Song
authors.affiliation: The 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Hematology, The 303 Hospital, Nanning, Guangxi, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Hematology, The 303 Hospital, Nanning, Guangxi, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Yin
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to Academy of Military Medical Sciences, The 307 Hospital, Beijing, China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Ning
authors.affiliation: State 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: The 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: The 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.
authors.forename: Yan-Ni
authors.initials: YN
authors.lastname: Ma
authors.affiliation: The 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.
authors.forename: Hua-Lu
authors.initials: HL
authors.lastname: Zhao
authors.affiliation: The 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.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: The 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.
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D064593:Heterografts; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099186:Histone Deacetylase 3
chemical_list: D048948:14-3-3 Proteins; D006655:Histone Deacetylases; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D000099186:Histone Deacetylase 3; C531201:MIRN451 microRNA, human; C572235:YWHAZ protein, human
keywords: HDAC3; YWHAZ; acute myeloid leukemia; c-Myc; microRNA-451