Journal
GENES & DEVELOPMENT
Volume 30, Issue 19, Pages 2187-2198Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.286112.116
Keywords
senescence; ARID1B; SWI/SNF; p53; ENTPD7; dNTP metabolism; cancer
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Funding
- Medical Research Council Centenary Award
- Instituto de Salud Carlos III-Redes Tematicas de Investigation Cooperativa en Salud grant [RD12/0036/0009]
- Medical Research Council [MC-A652-5PZ00, MC_U120085810]
- Children with Cancer UK [15-190] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [W1055] Funding Source: researchfish
- Medical Research Council [MR/M000125/1, MC_U120085810] Funding Source: researchfish
- MRC [MC_U120085810, MR/M000125/1] Funding Source: UKRI
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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 p16(INK4a) and p21(CIP1a) 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.
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