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

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 () and Xiongbin Lu ()
Additional contact information
Yujing Li: Shanghai University of Traditional Chinese Medicine
Yunhua Liu: The University of Texas MD Anderson Cancer Center
Hanchen Xu: Shanghai University of Traditional Chinese Medicine
Guanglong Jiang: Indiana University School of Medicine
Kevin Van der Jeught: The University of Texas MD Anderson Cancer Center
Yuanzhang Fang: The University of Texas MD Anderson Cancer Center
Zhuolong Zhou: Indiana University School of Medicine
Lu Zhang: The University of Texas MD Anderson Cancer Center
Michael Frieden: Indiana University School of Medicine
Lifei Wang: Indiana University School of Medicine
Zhenhua Luo: Cincinnati Children’s Hospital Medical Center
Milan Radovich: Indiana University School of Medicine
Bryan P. Schneider: Indiana University School of Medicine
Yibin Deng: The University of Minnesota Hormel Institute
Yunlong Liu: Indiana University School of Medicine
Kun Huang: Indiana University School of Medicine
Bin He: Houston Methodist Research Institute
Jin Wang: Baylor College of Medicine
Xiaoming He: University of Maryland
Xinna Zhang: Indiana University School of Medicine
Guang Ji: Shanghai University of Traditional Chinese Medicine
Xiongbin Lu: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06811-z

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