Genome-wide CRISPR screen reveals PSMA6 to be an essential gene in pancreatic cancer cells

Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is...

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Bibliographic Details
Published in:BMC cancer 2019-03, Vol.19 (1), p.253-12, Article 253
Main Authors: Bakke, Jesse, Wright, William C, Zamora, Anthony E, Oladimeji, Peter, Crawford, Jeremy Chase, Brewer, Christopher T, Autry, Robert J, Evans, William E, Thomas, Paul G, Chen, Taosheng
Format: Article
Language:English
Subjects:
Adenocarcinoma
Apoptosis
Bortezomib
Cancer cells
Cancer genetics
Cancer therapies
Carcinoma
Cell culture
CRISPR
CRISPR screen
Deoxyribonucleic acid
DNA
Endoplasmic reticulum
Essential genes
Flow cytometry
Gene mutation
Genes
Genetic aspects
Genetic screening
Genomes
Genomics
Kinases
Medical prognosis
Metastases
Mutation
Pancreatic cancer
Pancreatic carcinoma
PDAC
Proteasome inhibitors
Proteomics
PSMA6
siRNA
Therapeutic applications
Tumors
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Summary:Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is greatly needed. We used a negative-selection genome-wide CRISPR screen to identify essential genes in the PANC-1 human pancreatic carcinoma cell line. We validated the top hits with follow-up siRNA screens, using the HPNE, HPAF-II, AsPC-1, and Mia PaCa-2 cell lines. The PSMA6 gene was an identified candidate hit after the CRISPR screen, siRNA validation screen, and siRNA deconvolution screen. Spheroid formation assays and flow cytometry analysis showed that PSMA6 is critical for survival in many pancreatic ductal carcinoma cell models. Lastly, as PSMA6 protein is a proteosomal subunit of the 20S core complex, we showed that bortezomib, a proteasome inhibitor, was especially toxic in PANC-1 cells. Further study of PSMA6 and the proteasome subunit that it encodes, along with other hits identified in our CRISPR screens, may provide valuable insights into potential therapeutic targets for PDAC.
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-019-5455-1