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

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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Tordella L,Khan S,Hohmeyer A,Banito A,Klotz S,Raguz S,Martin N,Dhamarlingam G,Carroll T,González Meljem JM,Deswal S,Martínez-Barbera JP,García-Escudero R,Zuber J,Zender L,Gil J

doi

10.1101/gad.286112.116

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

2187-2198

issue

19

eissn

0890-9369

issn

1549-5477

pii

gad.286112.116

journal_volume

30

pub_type

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