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Title: Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
Author: Avgustinova, Alexandra
Symeonidi, Aikaterini
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Solé Boldo, Llorenç
Martín, Mercè
Pérez Rodríguez, Ivan
Prats, Neus
Lehner, Ben
Supek, Fran
Aznar Benitah, Salvador
Keywords: Epigenètica
Càncer de pell
Skin cancer
Issue Date: 1-Jan-2018
Publisher: Nature Publishing Group
Abstract: Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.
Note: versió postprint del document publicat a:
It is part of: Nature Cell Biology, 2018, Vol. 20, num. 12, p. 1400-1409
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ISSN: 1465-7392
Appears in Collections:Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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