Nicholas F Downing, Kaitlyn M Mills, Peter C Hollenhorst
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引用次数: 0
Abstract
Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60-70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5 or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. Here, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with PRC2. This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges the ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provides a mechanism for ERG synergy with PTEN deletion in prostate cancer. Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.
期刊介绍:
Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.