Format

Send to

Choose Destination
Nat Cell Biol. 2018 Dec;20(12):1400-1409. doi: 10.1038/s41556-018-0233-x. Epub 2018 Nov 19.

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours.

Author information

1
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. alexandra.avgustinova@irbbarcelona.org.
2
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
3
Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
4
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
5
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
6
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. fran.supek@irbbarcelona.org.
7
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. fran.supek@irbbarcelona.org.
8
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. salvador.aznar-benitah@irbbarcelona.org.
9
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. salvador.aznar-benitah@irbbarcelona.org.

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.

Comment in

PMID:
30455462
DOI:
10.1038/s41556-018-0233-x
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center