c-Myc suppresses miR-451⊣YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid leukemia

Oncotarget. 2016 Nov 22;7(47):77430-77443. doi: 10.18632/oncotarget.12679.

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.

Keywords: HDAC3; YWHAZ; acute myeloid leukemia; c-Myc; microRNA-451.

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism*
  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Gene Expression Regulation, Leukemic
  • Heterografts
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • MicroRNAs / genetics*
  • Models, Biological
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction

Substances

  • 14-3-3 Proteins
  • MIRN451 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • YWHAZ protein, human
  • Proto-Oncogene Proteins c-akt
  • Histone Deacetylases
  • histone deacetylase 3