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Clin Cancer Res. 2019 Sep 15;25(18):5608-5622. doi: 10.1158/1078-0432.CCR-18-2387. Epub 2019 Jul 2.

DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway.

Author information

1
Department of Radiation Oncology, University of California at San Francisco, CA.
2
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
3
Department of Radiation Oncology, University of Michigan-Ann Arbor, Ann Arbor, Michigan.
4
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
5
Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
6
Department of Radiation Oncology, OSF Healthcare, Peoria, Illinois.
7
Department of Medicine, University of California at San Francisco, San Francisco, California.
8
Department of Pathology, University of Michigan-Ann Arbor, Ann Arbor, Michigan.
9
Michigan Center for Translational Pathology, Ann Arbor, Michigan.
10
Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
11
Celgene Corporation, San Francisco, California.
12
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
13
Department of Urology, Mayo Clinic, Rochester, Minnesota.
14
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.
15
Memorial Sloan Kettering Cancer Center, New York, New York.
16
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
17
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
18
Department of Urology, University of California at San Francisco, San Francisco, California.
19
Department of Urology, University of Michigan-Ann Arbor, Ann Arbor, Michigan.
20
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Felix.Feng@ucsf.edu karen.knudsen@jefferson.edu.
21
Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
22
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
23
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
24
Department of Radiation Oncology, University of California at San Francisco, CA. Felix.Feng@ucsf.edu karen.knudsen@jefferson.edu.

Abstract

PURPOSE:

Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo.

RESULTS:

DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription.

CONCLUSIONS:

Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

PMID:
31266829
PMCID:
PMC6744969
[Available on 2020-03-15]
DOI:
10.1158/1078-0432.CCR-18-2387

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