Translational control of TOP2A influences doxorubicin efficacy

Mol Cell Biol. 2011 Sep;31(18):3790-801. doi: 10.1128/MCB.05639-11. Epub 2011 Jul 18.

Abstract

The cellular abundance of topoisomerase IIα (TOP2A) critically maintains DNA topology after replication and determines the efficacy of TOP2 inhibitors in chemotherapy. Here, we report that the RNA-binding protein HuR, commonly overexpressed in cancers, binds to the TOP2A 3'-untranslated region (3'UTR) and increases TOP2A translation. Reducing HuR levels triggered the recruitment of TOP2A transcripts to RNA-induced silencing complex (RISC) components and to cytoplasmic processing bodies. Using a novel MS2-tagged RNA precipitation method, we identified microRNA miR-548c-3p as a mediator of these effects and further uncovered that the interaction of miR-548c-3p with the TOP2A 3'UTR repressed TOP2A translation by antagonizing the action of HuR. Lowering TOP2A by silencing HuR or by overexpressing miR-548c-3p selectively decreased DNA damage after treatment with the chemotherapeutic agent doxorubicin. In sum, HuR enhances TOP2A translation by competing with miR-548c-3p; their combined actions control TOP2A expression levels and determine the effectiveness of doxorubicin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Antibiotics, Antineoplastic / pharmacology
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics*
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism*
  • DNA / metabolism
  • DNA Damage / drug effects
  • DNA Topoisomerases, Type II / biosynthesis
  • DNA Topoisomerases, Type II / genetics*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Doxorubicin / pharmacology*
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Poly-ADP-Ribose Binding Proteins
  • Protein Biosynthesis
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / biosynthesis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • RNA-Induced Silencing Complex / metabolism

Substances

  • 3' Untranslated Regions
  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm
  • Antigens, Surface
  • DNA-Binding Proteins
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • MIRN548 microRNA, human
  • MicroRNAs
  • Poly-ADP-Ribose Binding Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • RNA-Induced Silencing Complex
  • Doxorubicin
  • DNA
  • DNA Topoisomerases, Type II
  • TOP2A protein, human