Abstract
AbstractProstate cancer (PC) is the most common male visceral cancer, and second leading cause of cancer mortality in men in the Western world. Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre)Pten-deficient mouse model of PC, we identifiedArid1aloss as a driver in the development of metastatic disease. The insertion of transposon in theArid1agene resulted in a 60% reduction ofArid1aexpression, and reduced tumour free survival (SB:Ptenfl/flArid1aINTmedian 226 days vsSB:Ptenfl/flArid1aWT293 days, p=0.02),with elevated rates of metastasis (SB:Ptenfl/flArid1aINT75% lung metastasis rate vs 17%SB:Ptenfl/flArid1aWT,p<0.001 ). We further generated aPb-Cre Pten- andArid1a-deficient mouse model, in which loss ofArid1ademonstrated a profound acceleration in tumorigenesis inPtenfl/flmice compared toPtenloss alone (Pb-Cre Ptenfl/flArid1a+/+median survival of 267 days vs Pb-CrePtenfl/flArid1afl/fl103 days, p<0.0001). Our data revealed homozygousArid1aloss is required to dramatically accelerate prostate tumourigenesis, resulting in tumours with a less differentiated phenotype and a disorganised stroma. Furthermore,Arid1aloss mediated tumour formation in the mouse involved both the anterior and dorsolateral lobes, a unique feature fromPten-loss and other reported PC GEMM where tumour formation tends to be limited to the anterior lobes. Analysis of RNA and ChIP -Sequencing data suggestsArid1aloss 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.
Publisher
Cold Spring Harbor Laboratory