In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer.

Abstract

Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A-like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.

• Authors: Linda K Rushworth, Victoria Harle, Peter Repiscak, William Clark, Robin Shaw, Holly Hall, Martin Bushell, Hing Y Leung, Rachana Patel
• Journal: Life science alliance (Life Sci Alliance) Vol. 3 Issue 12 (12 2020) ISSN: 2575-1077 [Electronic] United States
• PMID: 33033111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Rushworth et al.

Chemical References

• DNA-Binding Proteins
• TCEAL1 protein, human
• Taxoids
• Transcription Factors
• Docetaxel

Topics

• Animals
• CRISPR-Cas Systems (genetics)
• Cell Line, Tumor
• Clustered Regularly Interspaced Short Palindromic Repeats (genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Docetaxel (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Genetic Engineering (methods)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (genetics, metabolism)
• Taxoids (pharmacology)
• Transcription Factors (genetics, metabolism)
• Xenograft Model Antitumor Assays (methods)