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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Yujing Li, Yunhua Liu, Hanchen Xu, Guanglong Jiang, Kevin Van der Jeught, Yuanzhang Fang, Zhuolong Zhou, Lu Zhang, Michael Frieden, Lifei Wang, Zhenhua Luo, Milan Radovich, Bryan P. Schneider, Yibin Deng, Yunlong Liu, Kun Huang, Bin He, Jin Wang, Xiaoming He, Xinna Zhang, Guang Ji, Xiongbin Lu

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. More... »

PAGES

4394

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-018-06811-z

DOI

http://dx.doi.org/10.1038/s41467-018-06811-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1107670538

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30349055


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445 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032, Shanghai, China
446 rdf:type schema:Organization
447 https://www.grid.ac/institutes/grid.39382.33 schema:alternateName Baylor College of Medicine
448 schema:name Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 77030, Houston, TX, USA
449 rdf:type schema:Organization
450 https://www.grid.ac/institutes/grid.412540.6 schema:alternateName Shanghai University of Traditional Chinese Medicine
451 schema:name Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032, Shanghai, China
452 rdf:type schema:Organization
453 https://www.grid.ac/institutes/grid.63368.38 schema:alternateName Houston Methodist
454 schema:name Biomarker Research Program Center, Houston Methodist Research Institute, 77030, Houston, TX, USA
455 rdf:type schema:Organization
 




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