Tordella, L;
Khan, S;
Hohmeyer, A;
Banito, A;
Klotz, S;
Raguz, S;
Martin, N;
... Gil, J; + view all
(2016)
SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.
Genes & Development
, 30
(19)
pp. 2187-2198.
10.1101/gad.286112.116.
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Abstract
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
| Type: | Article |
|---|---|
| Title: | SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1101/gad.286112.116 |
| Publisher version: | http://dx.doi.org/10.1101/gad.286112.116 |
| Language: | English |
| Additional information: | Copyright © 2016 Tordella et al. This article, published in Genes&Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | senescence; ARID1B; SWI/SNF; p53; ENTPD7; dNTP metabolism; cancer |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1541154 |
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