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

Abstract

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/flArid1a^+/+ 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.