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    Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II

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    Author
    Li, Y.
    Liu, Y.
    Xu, H.
    Date
    2018
    Journal
    Nature Communications
    Publisher
    Nature Publishing Group
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1038/s41467-018-06811-z
    Abstract
    Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p. Copyright 2018, The Author(s).
    Keyword
    metastatic castration-resistant prostate cancer (CRPC)
    RNA Polymerase II--antagonists & inhibitors
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85055141917&doi=10.1038%2fs41467-018-06811-z&partnerID=40&md5=01e741047d30f0daf23b569d88a39cfb; http://hdl.handle.net/10713/9732
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-018-06811-z
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    UMB Open Access Articles 2018

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