DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

Vishal Kothari; Jonathan F. Goodwin; Shuang G. Zhao; Justin M. Drake; Yi Yin; S. Laura Chang; Joseph R. Evans; Kari Wilder-Romans; Kristina Gabbara; Emanuela Dylgjeri; Jonathan Chou; Grace Sun; Scott A. Tomlins; Rohit Mehra; Kristen Hege; Ellen H. Filvaroff; Edward M. Schaeffer; R. Jeffrey Karnes; David A. Quigley; Dana E. Rathkopf; Housheng H. He; Corey Speers; Daniel E. Spratt; Luke A. Gilbert; Alan Ashworth; Arul M. Chinnaiyan; Ganesh V. Raj; Karen E. Knudsen; Felix Y. Feng

doi:10.1158/1078-0432.CCR-18-2387

DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

Vishal Kothari, Jonathan F. Goodwin, Shuang G. Zhao, Justin M. Drake, Yi Yin, S. Laura Chang, Joseph R. Evans, Kari Wilder-Romans, Kristina Gabbara, Emanuela Dylgjeri, Jonathan Chou, Grace Sun, Scott A. Tomlins, Rohit Mehra, Kristen Hege, Ellen H. Filvaroff, Edward M. Schaeffer, R. Jeffrey Karnes, David A. Quigley, Dana E. RathkopfHousheng H. He, Corey Speers, Daniel E. Spratt, Luke A. Gilbert, Alan Ashworth, Arul M. Chinnaiyan, Ganesh V. Raj, Karen E. Knudsen, Felix Y. Feng

Pharmacology

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17 Scopus citations

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 longterm 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 ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Original language	English (US)
Pages (from-to)	5608-5622
Number of pages	15
Journal	Clinical Cancer Research
Volume	25
Issue number	18
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-2387
State	Published - Sep 15 2019

Bibliographical note

Funding Information:
This work was supported by a grant to V. Kothari and S.G. Zhao from the PCF, to F.Y. Feng, K.E. Knudsen and S.A. Tomlins from the PCF/Evans Foundation, K.E. Knudsen from PA CURE and NCI (CA159945, CA176401), F.Y. Feng and V. Kothari from the DOD PCa Idea Development Award No. W81XWH1810599

Publisher Copyright:
© 2019 American Association for Cancer Research.

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Kothari, V., Goodwin, J. F., Zhao, S. G., Drake, J. M., Yin, Y., Chang, S. L., Evans, J. R., Wilder-Romans, K., Gabbara, K., Dylgjeri, E., Chou, J., Sun, G., Tomlins, S. A., Mehra, R., Hege, K., Filvaroff, E. H., Schaeffer, E. M., Karnes, R. J., Quigley, D. A., ... Feng, F. Y. (2019). DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway. Clinical Cancer Research, 25(18), 5608-5622. https://doi.org/10.1158/1078-0432.CCR-18-2387

Kothari, V, Goodwin, JF, Zhao, SG, Drake, JM, Yin, Y, Chang, SL, Evans, JR, Wilder-Romans, K, Gabbara, K, Dylgjeri, E, Chou, J, Sun, G, Tomlins, SA, Mehra, R, Hege, K, Filvaroff, EH, Schaeffer, EM, Karnes, RJ, Quigley, DA, Rathkopf, DE, He, HH, Speers, C, Spratt, DE, Gilbert, LA, Ashworth, A, Chinnaiyan, AM, Raj, GV, Knudsen, KE & Feng, FY 2019, 'DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway', Clinical Cancer Research, vol. 25, no. 18, pp. 5608-5622. https://doi.org/10.1158/1078-0432.CCR-18-2387

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title = "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 longterm 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 ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.",

author = "Vishal Kothari and Goodwin, {Jonathan F.} and Zhao, {Shuang G.} and Drake, {Justin M.} and Yi Yin and Chang, {S. Laura} and Evans, {Joseph R.} and Kari Wilder-Romans and Kristina Gabbara and Emanuela Dylgjeri and Jonathan Chou and Grace Sun and Tomlins, {Scott A.} and Rohit Mehra and Kristen Hege and Filvaroff, {Ellen H.} and Schaeffer, {Edward M.} and Karnes, {R. Jeffrey} and Quigley, {David A.} and Rathkopf, {Dana E.} and He, {Housheng H.} and Corey Speers and Spratt, {Daniel E.} and Gilbert, {Luke A.} and Alan Ashworth and Chinnaiyan, {Arul M.} and Raj, {Ganesh V.} and Knudsen, {Karen E.} and Feng, {Felix Y.}",

note = "Funding Information: This work was supported by a grant to V. Kothari and S.G. Zhao from the PCF, to F.Y. Feng, K.E. Knudsen and S.A. Tomlins from the PCF/Evans Foundation, K.E. Knudsen from PA CURE and NCI (CA159945, CA176401), F.Y. Feng and V. Kothari from the DOD PCa Idea Development Award No. W81XWH1810599 Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

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AU - Kothari, Vishal

AU - Goodwin, Jonathan F.

AU - Zhao, Shuang G.

AU - Drake, Justin M.

AU - Yin, Yi

AU - Chang, S. Laura

AU - Evans, Joseph R.

AU - Wilder-Romans, Kari

AU - Gabbara, Kristina

AU - Dylgjeri, Emanuela

AU - Chou, Jonathan

AU - Sun, Grace

AU - Tomlins, Scott A.

AU - Mehra, Rohit

AU - Hege, Kristen

AU - Filvaroff, Ellen H.

AU - Schaeffer, Edward M.

AU - Karnes, R. Jeffrey

AU - Quigley, David A.

AU - Rathkopf, Dana E.

AU - He, Housheng H.

AU - Speers, Corey

AU - Spratt, Daniel E.

AU - Gilbert, Luke A.

AU - Ashworth, Alan

AU - Chinnaiyan, Arul M.

AU - Raj, Ganesh V.

AU - Knudsen, Karen E.

AU - Feng, Felix Y.

N1 - Funding Information: This work was supported by a grant to V. Kothari and S.G. Zhao from the PCF, to F.Y. Feng, K.E. Knudsen and S.A. Tomlins from the PCF/Evans Foundation, K.E. Knudsen from PA CURE and NCI (CA159945, CA176401), F.Y. Feng and V. Kothari from the DOD PCa Idea Development Award No. W81XWH1810599 Publisher Copyright: © 2019 American Association for Cancer Research.

PY - 2019/9/15

Y1 - 2019/9/15

N2 - 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 longterm 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 ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

AB - 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 longterm 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 ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

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DNA-dependent protein kinase drives prostate cancer progression through transcriptional regulation of the Wnt signaling pathway

Abstract

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