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


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.

SUBMITTER: Kothari V 

PROVIDER: S-EPMC6744969 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Kothari Vishal V   Goodwin Jonathan F JF   Zhao Shuang G SG   Drake Justin M JM   Yin Yi Y   Chang S Laura SL   Evans Joseph R JR   Wilder-Romans Kari K   Gabbara Kristina K   Dylgjeri Emanuela E   Chou Jonathan J   Sun Grace G   Tomlins Scott A SA   Mehra Rohit R   Hege Kristen K   Filvaroff Ellen H EH   Schaeffer Edward M EM   Karnes R Jeffrey RJ   Quigley David A DA   Rathkopf Dana E DE   He Housheng H HH   Speers Corey C   Spratt Daniel E DE   Gilbert Luke A LA   Ashworth Alan A   Chinnaiyan Arul M AM   Raj Ganesh V GV   Knudsen Karen E KE   Feng Felix Y FY  

Clinical cancer research : an official journal of the American Association for Cancer Research 20190702 18


<h4>Purpose</h4>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.<b>Experimental Design:</b> 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 fro  ...[more]

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