Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos
Menée notamment à l'aide de modèles murins de cancer de la prostate, cette étude met en évidence un mécanisme par lequel la perte d'expression du gène Arid1a accélère la tumorigenèse via le renforcement de la fonction de la sous-unité cFos du facteur de transcription AP1
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.
British Journal of Cancer , article en libre accès, 2025