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.
Highlights
The extensive sequencing of cancer genomes has provided a comprehensive list of the recurrent genetic alterations observed in different tumor types
Similar to what we observed when using an shRNA targeting Ink4a/Arf (Supplemental Fig. S1C), knockdown of Arid1b blunted replicative senescence, as evidenced by increased colony formation, a higher percentage of cells incorporating BrdU, and a decrease in the percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells when compared with control mouse embryonic fibroblasts (MEFs) (Fig. 1C)
We tested whether knockdown of Arid1b expression protected MEFs against senescence induced by oncogenic RAS
Summary
The extensive sequencing of cancer genomes has provided a comprehensive list of the recurrent genetic alterations observed in different tumor types. GENES & DEVELOPMENT 30:2187–2198 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org program that includes the implementation of a highly stable cell cycle arrest and profound changes in transcription, metabolism, secretome, and chromatin organization (Kuilman et al 2010) Many of these senescent phenotypes are under epigenetic control (Kia et al 2008; Barradas et al 2009). Genes encoding for components of the SWI/SNF chromatin remodeling complex are frequently deleted or mutated across a wide spectrum of cancers (Kadoch et al 2013). This suggests that SWI/SNF plays a fundamental protective role toward tumorigenesis via the regulation of basic cellular functions. In HCC, >20% of the tumors present alterations in SWI/SNF components, and mutations in ARID1B are second only to ARID1A in frequency (Fujimoto et al 2012)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call