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dc.contributor.authorLi, Y.
dc.contributor.authorLiu, Y.
dc.contributor.authorXu, H.
dc.date.accessioned2019-06-21T18:46:29Z
dc.date.available2019-06-21T18:46:29Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85055141917&doi=10.1038%2fs41467-018-06811-z&partnerID=40&md5=01e741047d30f0daf23b569d88a39cfb
dc.identifier.urihttp://hdl.handle.net/10713/9732
dc.description.abstractHeterozygous 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).en_US
dc.description.urihttps://dx.doi.org/10.1038/s41467-018-06811-zen_US
dc.language.isoen-USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofNature Communications
dc.subjectmetastatic castration-resistant prostate cancer (CRPC)en_US
dc.subject.meshRNA Polymerase II--antagonists & inhibitorsen_US
dc.titleHeterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase IIen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41467-018-06811-z
dc.identifier.pmid30349055


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