Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Abstract

AbstractPhenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance in androgen indifferent prostate tumors. It is critical to identify mechanisms and actionable targets driving phenotypic plasticity. Here, we report that loss of tristetraprolin (TTP, geneZFP36), an RNA binding protein that regulates mRNA stability increases NF-κB activation and is associated with higher rates of aggressive disease and early recurrence in primary prostate cancer (PCa). We examined the clinical and biological impact ofZFP36loss combined withPTENloss, a known driver of PCa. Combined loss ofPTENandZFP36expression was associated with increased risk of recurrence in multiple independent primary PCa cohorts, and significantly reduced overall survival and time to progression following castration in genetically engineered mouse models.ZFP36loss alters the cell state that is driven byPTENloss, demonstrated by positive enrichment of gene sets including EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3.ZFP36loss also induces enrichment of multiple gene sets involved in cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide induced significant therapeutic responses in tumors withPTENandZFP36co-loss and reversed castration resistance. This work identifies a novel molecular mechanism driving phenotypic plasticity and castration resistance through loss ofZFP36expression, that can be reversed by inhibition of NF-κB activity.