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; Xiongbin Lu

doi:10.1038/s41467-018-06811-z

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 ZhangGuang Ji, Xiongbin Lu

Hormel Institute

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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.

Original language	English (US)
Article number	4394
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06811-z
State	Published - Dec 1 2018

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Publisher Copyright:
© 2018, The Author(s).

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Research Support, Non-U.S. Gov't

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Li, Y., Liu, Y., Xu, H., Jiang, G., Van der Jeught, K., Fang, Y., Zhou, Z., Zhang, L., Frieden, M., Wang, L., Luo, Z., Radovich, M., Schneider, B. P., Deng, Y., Liu, Y., Huang, K., He, B., Wang, J., He, X., ... Lu, X. (2018). Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nature communications, 9(1), Article 4394. https://doi.org/10.1038/s41467-018-06811-z

Li, Y, Liu, Y, Xu, H, Jiang, G, Van der Jeught, K, Fang, Y, Zhou, Z, Zhang, L, Frieden, M, Wang, L, Luo, Z, Radovich, M, Schneider, BP, Deng, Y, Liu, Y, Huang, K, He, B, Wang, J, He, X, Zhang, X, Ji, G & Lu, X 2018, 'Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II', Nature communications, vol. 9, no. 1, 4394. https://doi.org/10.1038/s41467-018-06811-z

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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.",

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

Abstract

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