Cyclin D1 induction of Dicer governs microRNA processing and expression in breast cancer

Nat Commun. 2013:4:2812. doi: 10.1038/ncomms3812.

Abstract

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates the pRB protein and promotes G1/S cell-cycle progression and oncogenesis. Dicer is a central regulator of miRNA maturation, encoding an enzyme that cleaves double-stranded RNA or stem-loop-stem RNA into 20-25 nucleotide long small RNA, governing sequence-specific gene silencing and heterochromatin methylation. The mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Here we show that cyclin D1(-/-) cells are defective in pre-miRNA processing which is restored by cyclin D1a rescue. Cyclin D1 induces Dicer expression in vitro and in vivo. Dicer is transcriptionally targeted by cyclin D1, via a cdk-independent mechanism. Cyclin D1 and Dicer expression significantly correlates in luminal A and basal-like subtypes of human breast cancer. Cyclin D1 and Dicer maintain heterochromatic histone modification (Tri-m-H3K9). Cyclin D1-mediated cellular proliferation and migration is Dicer-dependent. We conclude that cyclin D1 induction of Dicer coordinates microRNA biogenesis.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Movement / genetics
  • Cell Proliferation
  • Cyclin D1 / physiology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HCT116 Cells
  • Histones / metabolism
  • Humans
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / enzymology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Protein Processing, Post-Translational / genetics
  • Ribonuclease III / metabolism*

Substances

  • Histones
  • MicroRNAs
  • Cyclin D1
  • Ribonuclease III