Nature communications, 2018-10, Vol.9 (1), p.4394-15, Article 4394
2018
Details
- Autor(en) / Beteiligte
- Titel
- Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II
- Ist Teil von
- Nature communications, 2018-10, Vol.9 (1), p.4394-15, Article 4394
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-06811-zTitel-ID: cdi_doaj_primary_oai_doaj_org_article_4b210d41ca154f21b5a6e78a1b6ae6c9
- Format
- –
- Schlagworte
- Amanitin, Apoptosis - genetics, Apoptosis - physiology, Cancer, Carrier Proteins - genetics, Carrier Proteins - metabolism, Castration, Catalysis, Cell Line, Tumor, Cell Survival - genetics, Cell Survival - physiology, Chromosome 17, Chromosome deletion, Chromosomes, Human, Pair 17 - genetics, Chromosomes, Human, Pair 17 - metabolism, Clonal deletion, CRISPR, Dependence, DNA-directed RNA polymerase, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Inhibition, Male, Metastases, p53 Protein, Prostate, Prostate cancer, Prostatic Neoplasms, Castration-Resistant - genetics, Prostatic Neoplasms, Castration-Resistant - metabolism, Ribonucleic acid, RNA, RNA polymerase, RNA polymerase II, RNA Polymerase II - genetics, RNA Polymerase II - metabolism, Sequence Deletion - genetics, Sequence Deletion - physiology, Therapeutic applications, Transcription, Transcription, Genetic - genetics, Transcription, Genetic - physiology, Tumor suppressor genes, Ubiquitin, Ubiquitin-protein ligase, Ubiquitin-Protein Ligases, Ubiquitination