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.