Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos.

BACKGROUND: Prostate cancer (PC) is the commonest male visceral cancer, and second leading cause of cancer mortality in men in the Western world. METHODS: Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre) Pten-deficient mouse model of PC, we identified Arid1a loss as a driver in the development of metastatic disease. RESULTS: The insertion of transposon in the Arid1a gene resulted in a 60% reduction of Arid1a expression, and reduced tumour free survival (SB:Pten(fl/fl) Arid1a(INT) median 226 days vs SB:Pten(fl/fl) Arid1a(WT) 293 days, p = 0.02),with elevated rates of metastasis (SB:Pten(fl/fl) Arid1a(INT) 75% lung metastasis rate vs 17% SB:Pten(fl/fl) Arid1a(WT), p < 0.001). We further generated a Pb-Cre Pten- and Arid1a-deficient mouse model, in which loss of Arid1a demonstrated a profound acceleration in tumorigenesis in Pten(fl/fl) mice compared to Pten loss alone (Pb-Cre Pten(fl/fl)Arid1a(+/+) median survival of 267 days vs Pb-Cre Pten(fl/fl) Arid1a(fl/fl) 103 days, p < 0.0001). CONCLUSION: Our data revealed homozygous Arid1a loss is required to dramatically accelerate prostate tumourigenesis. Analysis of RNA and ChIP -Sequencing data suggests Arid1a loss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.