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

Author:

Hartley Andrew,Galbraith Laura C.A.,Shaw Robin,Tibbo Amy,Veeratterapillay Rajan,Wilson Laura,Heer RakeshORCID,Blyth Karen,Leung Hing,Ahmad ImranORCID

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

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3