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Comprehensive silencing of target-sharing microRNAs is a mechanism for SIRT1 overexpression in cancer

Kotaro Kiga1, Yoko Fukuda-Yuzawa, Masanobu Tanabe

  • 1a Max-Planck-Institute of Immunobiology and Epigenetics ; Freiburg , Germany.

RNA Biology
|December 9, 2014
PubMed

Insights

Cancer-related SIRT1 overexpression stems from silenced microRNAs (miRNAs) that normally repress Sirt1 mRNA. Aberrant DNA methylation silences these miRNAs, leading to elevated SIRT1 in malignancies.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Sirtuin 1 (SIRT1) overexpression is common in cancers, but its cause is unclear.
  • Understanding SIRT1's role in malignancies is crucial for cancer therapy.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind SIRT1 overexpression in cancer.
  • To identify the regulatory elements responsible for elevated SIRT1 levels.

Main Methods:

  • Comprehensive library-based screening for Sirt1-targeting microRNAs (miRNAs).
  • miRNA gene profiling to assess expression patterns.
  • Analysis of CpG island association and DNA methylation.

Main Results:

  • SIRT1 overexpression is caused by the evasion of Sirt1 mRNA from miRNA-mediated repression.
  • A group of Sirt1-targeting miRNAs are silenced in cancer.
  • These miRNA genes exhibit broad expression patterns and CpG island association, suggesting DNA methylation as the silencing mechanism.
  • This study demonstrates group-wide miRNA regulation via epigenetic mechanisms targeting common key genes.

Conclusions:

  • Aberrant CpG DNA methylation silences tumor-suppressive miRNAs, leading to SIRT1 overexpression in cancer.
  • Epigenetic silencing of miRNAs is a key mechanism driving malignant SIRT1 elevation.
  • This provides a novel insight into cancer-related gene regulation by miRNAs and epigenetics.
Keywords:
3′UTR, 3′ untranslated region5-Aza-dC, 5-aza-2’-deoxycytidineCGIs, CpG islandsDNA methylationE2F1, E2F transcription factor 1FOXO, forkhead box OHIC1, hypermethylated in cancer 1LXR, liver X receptorMicroRNAMyoD, myogenic differentiation 1NAD, nicotinamide adenine dinucleotideNF-κB, nuclear factor kappa-BOVCA1, ovarian cancer-associated gene 1 proteinOVCA2, ovarian cancer-associated gene 2 proteinPARP, poly(ADP-ribose) polymerase-1PGC-1α, peroxisome proliferative activated receptor, gamma, coactivator 1 alphaPUMA, p53-upregulated modulator of apoptosisSIRT1SIRT1, sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)SMG6, smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)Sir2, Silent information regulator 2cancerepigeneticsp53, protein 53pri-miRNA, primary miRNA

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