Myc overexpression brings out unexpected antiapoptotic effects of miR-34a

Oncogene. 2011 Jun 2;30(22):2587-94. doi: 10.1038/onc.2010.634. Epub 2011 Feb 7.


Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf-Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / genetics*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Pyrazines / pharmacology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*


  • Antineoplastic Agents
  • Boronic Acids
  • MIRN34 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Pyrazines
  • Tumor Suppressor Protein p53
  • Bortezomib
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • ADP-Ribosylation Factors