title: Comprehensive silencing of target-sharing microRNAs is a mechanism for SIRT1 overexpression in cancer.
abstract: Overexpression of SIRT1 is frequently observed in various types of cancers, suggesting its potential role in malignancies. However, the molecular basis of how SIRT1 is elevated in cancer is less understood. Here we show that cancer-related SIRT1 overexpression is due to evasion of Sirt1 mRNA from repression by a group of Sirt1-targeting microRNAs (miRNAs) that might be robustly silenced in cancer. Our comprehensive library-based screening and subsequent miRNA gene profiling revealed a housekeeping gene-like broad expression pattern and strong CpG island-association of the Sirt1-targeting miRNA genes. This suggests aberrant CpG DNA methylation as the mechanistic background for malignant SIRT1 elevation. Our work also provides an example where epigenetic mechanisms cause the group-wide regulation of miRNAs sharing a common key target.
authors.affiliation: a Max-Planck-Institute of Immunobiology and Epigenetics ; Freiburg , Germany.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kiga
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda-Yuzawa
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tanabe
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
authors.forename: Taro
authors.initials: T
authors.lastname: Fukao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005047:Etoposide / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; C547077:MIRN132 microRNA, human; C551411:MIRN212 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: 3′UTR, 3′ untranslated region; 5-Aza-dC, 5-aza-2’-deoxycytidine; CGIs, CpG islands; DNA methylation; E2F1, E2F transcription factor 1; FOXO, forkhead box O; HIC1, hypermethylated in cancer 1; LXR, liver X receptor; MicroRNA; MyoD, myogenic differentiation 1; NAD, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-B; OVCA1, ovarian cancer-associated gene 1 protein; OVCA2, ovarian cancer-associated gene 2 protein; PARP, poly(ADP-ribose) polymerase-1; PGC-1α, peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PUMA, p53-upregulated modulator of apoptosis; SIRT1; SIRT1, 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 2; cancer; epigenetics; p53, protein 53; pri-miRNA, primary miRNA