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.
Bibliographical noteFunding Information:
We thank E. Lander and D. Sabatini for providing the Cas9 expressing vector and CRISPR pooled library. We thank L. Huang and M. Bar-Eli for lentivirus production. We also thank J. Wang for technical support in prostate orthotopic tumor experiments. The following cores were used: MD Anderson Flow Cytometry and Cellular Imaging Core, MD Anderson Clinical Pathology, Veterinary Medicine and Surgery Core, MD Anderson Sequencing and Microarray Core, ICBM Core Facility at IUSM. This work was supported in part by US National Institutes of Health grants R01CA203737 (X.L.), R01CA206366 (X.H. and X.L.), R01CA211861 (B.H.), and R21CA213535 (J.W. and X.L.), and by Indiana University Strategic Research Initiative fund (X.L.), Vera Bradley Foundation for Breast Cancer Research (X.L. and X.Z.) and American Cancer Society Institutional Research Grant (Yunhua Liu).
© 2018, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't