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Background <p>Prostate cancer (PC) is the commonest male visceral cancer, and second leading cause of cancer mortality in men in the Western world.</p> Methods <p>Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (<i>Pb-Cre</i>) <i>Pten</i>-deficient mouse model of PC, we identified <i>Arid1a</i> loss as a driver in the development of metastatic disease.</p> Results <p>The insertion of transposon in the <i>Arid1a</i> gene resulted in a 60% reduction of <i>Arid1a</i> expression, and reduced tumour free survival (<i>SB:Pten</i><sup><i>fl/fl</i></sup> <i>Arid1a</i><sup><i>INT</i></sup> median 226 days vs <i>SB:Pten</i><sup><i>fl/fl</i></sup> <i>Arid1a</i><sup><i>WT</i></sup> 293 days, <i>p</i> = 0.02),with elevated rates of metastasis (<i>SB:Pten</i><sup><i>fl/fl</i></sup> <i>Arid1a</i><sup><i>INT</i></sup> 75% lung metastasis rate vs 17% <i>SB:Pten</i><sup><i>fl/fl</i></sup> <i>Arid1a</i><sup><i>WT</i></sup>, <i>p</i> &lt; 0.001). We further generated a <i>Pb-Cre Pten</i>- and <i>Arid1a</i>-deficient mouse model, in which loss of <i>Arid1a</i> demonstrated a profound acceleration in tumorigenesis in <i>Pten</i><sup><i>fl/fl</i></sup> mice compared to <i>Pten</i> loss alone (<i>Pb-Cre Pten</i><sup><i>fl/fl</i></sup><i>Arid1a</i><sup><i>+/+</i></sup> median survival of 267 days vs Pb-Cre <i>Pten</i><sup><i>fl/fl</i></sup> <i>Arid1a</i><sup><i>fl/fl</i></sup> 103 days, <i>p</i> &lt; 0.0001).</p> Conclusion <p>Our data revealed homozygous <i>Arid1a</i> loss is required to dramatically accelerate prostate tumourigenesis. Analysis of RNA and ChIP -Sequencing data suggests <i>Arid1a</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月30日

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

摘要

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:Ptenfl/fl Arid1aINT median 226 days vs SB:Ptenfl/fl Arid1aWT 293 days, p = 0.02),with elevated rates of metastasis (SB:Ptenfl/fl Arid1aINT 75% lung metastasis rate vs 17% SB:Ptenfl/fl Arid1aWT, 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 Ptenfl/fl mice compared to Pten loss alone (Pb-Cre Ptenfl/flArid1a+/+ median survival of 267 days vs Pb-Cre Ptenfl/fl Arid1afl/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.