SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

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Title: SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer
Author(s): Tordella, L
Khan, S
Hohmeyer, A
Banito, A
Klotz, S
Raguz, S
Martin, N
Ghamarlingam, G
Carroll, T
Gonzalez Meljem, JM
Deswal, S
Pedro, J
Martinez-Barbero, JP
Garcia-Escudero, R
Zuber, J
Zender, L
Gil, J
Item Type: Journal Article
Abstract: Oncogene-induced senescence (OIS) is a potent tumour 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 tumours. 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 pro-senescence therapies could be employed against SWI/SNF-mutated cancers.
Publication Date: 13-Oct-2016
Date of Acceptance: 13-Sep-2016
URI: http://hdl.handle.net/10044/1/40279
DOI: https://dx.doi.org/10.1101/gad.286112.116
ISSN: 1549-5477
Publisher: Cold Spring Harbor Laboratory Press
Start Page: 2187-2198
End Page: 2187-2198
Journal / Book Title: Genes & Development
Volume: 30
Issue: 19
Copyright Statement: © 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: ARID1B
ENTPD7
SWI/SNF
cancer
dNTP metabolism
p53
senescence
Developmental Biology
Biological Sciences
Medical And Health Sciences
Psychology And Cognitive Sciences
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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