MiR-221/222 target the DNA methyltransferase MGMT in glioma cells

PLoS One. 2013 Sep 19;8(9):e74466. doi: 10.1371/journal.pone.0074466. eCollection 2013.

Abstract

Glioblastoma multiforme (GBM) is one of the most deadly types of cancer. To date, the best clinical approach for treatment is based on administration of temozolomide (TMZ) in combination with radiotherapy. Much evidence suggests that the intracellular level of the alkylating enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) impacts response to TMZ in GBM patients. MGMT expression is regulated by the methylation of its promoter. However, evidence indicates that this is not the only regulatory mechanism present. Here, we describe a hitherto unknown microRNA-mediated mechanism of MGMT expression regulation. We show that miR-221 and miR-222 are upregulated in GMB patients and that these paralogues target MGMT mRNA, inducing greater TMZ-mediated cell death. However, miR-221/miR-222 also increase DNA damage and, thus, chromosomal rearrangements. Indeed, miR-221 overexpression in glioma cells led to an increase in markers of DNA damage, an effect rescued by re-expression of MGMT. Thus, chronic miR-221/222-mediated MGMT downregulation may render cells unable to repair genetic damage. This, associated also to miR-221/222 oncogenic potential, may poor GBM prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis / genetics
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • DNA Modification Methylases / genetics*
  • DNA Repair Enzymes / genetics*
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics*
  • Glioma / metabolism
  • Humans
  • MicroRNAs / genetics*
  • RNA Interference*
  • RNA, Messenger / genetics*
  • Temozolomide
  • Tumor Suppressor Proteins / genetics*

Substances

  • Antineoplastic Agents, Alkylating
  • MIRN221 microRNA, human
  • MIRN222 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide

Grants and funding

This work was partially supported by funds from Associazione Italiana Ricerca sul Cancro, to GC (grant n.ro 10620), MERIT (RBNE08E8CZ_002) to GC, POR Campania FSE 2007-2013, Project CRÈME to GC. CQ and MI was supported by the “Federazione Italiana Ricerca sul Cancro” Post-Doctoral Research Fellowship. GR was supported by a MERIT project Fellowship. ADL was supported by the Angeles Alvariño-2009 postdoctoral fellowship from the Xunta de Galicia and European Social Fund and at present is the recipient of a Sara Borrell postdoctoral contract (CD12/00738) from the Instituto de Salud Carlos III at the Spanish Ministry of Economy and Competitiveness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.