DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

Jonathan F. Goodwin; Vishal Kothari; Justin M. Drake; Shuang Zhao; Emanuela Dylgjeri; Jeffry L. Dean; Matthew J. Schiewer; Christopher McNair; Jennifer K. Jones; Alvaro Aytes; Michael S. Magee; Adam E. Snook; Ziqi Zhu; Robert B. Den; Ruth C. Birbe; Leonard G. Gomella; Nicholas A. Graham; Ajay A. Vashisht; James A. Wohlschlegel; Thomas G. Graeber; R. Jeffrey Karnes; Mandeep Takhar; Elai Davicioni; Scott A. Tomlins; Cory Abate-Shen; Nima Sharifi; Owen N. Witte; Felix Y. Feng; Karen E. Knudsen

doi:10.1016/j.ccell.2015.06.004

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

Jonathan F. Goodwin, Vishal Kothari, Justin M. Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher McNair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert B. Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. GraeberR. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

143 Scopus citations

Abstract

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, invitro and invivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies. Goodwin etal. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.

Original language	English (US)
Pages (from-to)	97-113
Number of pages	17
Journal	Cancer cell
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2015.06.004
State	Published - Jul 13 2015

Funding

The authors thank Dr. A. Fatatis and T.J. Stanek for reagents, and N. Erho (GenomeDx) and members of the K.E.K. laboratory for input. This work was supported by grants from PCF (to M.J.S.); PCF/Movember and Evans Foundation (to F.Y.F., S.A.T., and K.E.K.); PA CURE and NCI CA159945, CA176401 (to K.E.K.); DOD PCa Research program W81XWH-14-1-0148 (to J.M.D.); UCLA SOMI and NIH R25T CA098010 (to N.A.G.); NIH GM089778 (to J.A.W.); NCI CA168585 and ACS RSG-12-257-01-TBE (to T.G.G.); NCATS UCLA UL1TR000124 (to T.G.G. and O.N.W.); PCF (to O.N.W.); and NCI CA173481, CA183929 (to C.A.-S.). O.N.W. is an Investigator of the Howard Hughes Medical Institute and partially supported by a Stand Up to Cancer-PCF-Prostate Dream Team Translational Cancer Research Grant (co-PI), a grant made possible through the Movember Foundation. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by AACR. K.E.K. receives research support from Celgene.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.06.004

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Goodwin, J. F., Kothari, V., Drake, J. M., Zhao, S., Dylgjeri, E., Dean, J. L., Schiewer, M. J., McNair, C., Jones, J. K., Aytes, A., Magee, M. S., Snook, A. E., Zhu, Z., Den, R. B., Birbe, R. C., Gomella, L. G., Graham, N. A., Vashisht, A. A., Wohlschlegel, J. A., ... Knudsen, K. E. (2015). DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. Cancer cell, 28(1), 97-113. https://doi.org/10.1016/j.ccell.2015.06.004

@article{37931a24093b45bdaa8d9ac9de9c2f81,

title = "DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis",

abstract = "Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, invitro and invivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies. Goodwin etal. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.",

author = "Goodwin, {Jonathan F.} and Vishal Kothari and Drake, {Justin M.} and Shuang Zhao and Emanuela Dylgjeri and Dean, {Jeffry L.} and Schiewer, {Matthew J.} and Christopher McNair and Jones, {Jennifer K.} and Alvaro Aytes and Magee, {Michael S.} and Snook, {Adam E.} and Ziqi Zhu and Den, {Robert B.} and Birbe, {Ruth C.} and Gomella, {Leonard G.} and Graham, {Nicholas A.} and Vashisht, {Ajay A.} and Wohlschlegel, {James A.} and Graeber, {Thomas G.} and Karnes, {R. Jeffrey} and Mandeep Takhar and Elai Davicioni and Tomlins, {Scott A.} and Cory Abate-Shen and Nima Sharifi and Witte, {Owen N.} and Feng, {Felix Y.} and Knudsen, {Karen E.}",

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Goodwin, JF, Kothari, V, Drake, JM, Zhao, S, Dylgjeri, E, Dean, JL, Schiewer, MJ, McNair, C, Jones, JK, Aytes, A, Magee, MS, Snook, AE, Zhu, Z, Den, RB, Birbe, RC, Gomella, LG, Graham, NA, Vashisht, AA, Wohlschlegel, JA, Graeber, TG, Karnes, RJ, Takhar, M, Davicioni, E, Tomlins, SA, Abate-Shen, C, Sharifi, N, Witte, ON, Feng, FY & Knudsen, KE 2015, 'DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis', Cancer cell, vol. 28, no. 1, pp. 97-113. https://doi.org/10.1016/j.ccell.2015.06.004

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T1 - DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

AU - Goodwin, Jonathan F.

AU - Kothari, Vishal

AU - Drake, Justin M.

AU - Zhao, Shuang

AU - Dylgjeri, Emanuela

AU - Dean, Jeffry L.

AU - Schiewer, Matthew J.

AU - McNair, Christopher

AU - Jones, Jennifer K.

AU - Aytes, Alvaro

AU - Magee, Michael S.

AU - Snook, Adam E.

AU - Zhu, Ziqi

AU - Den, Robert B.

AU - Birbe, Ruth C.

AU - Gomella, Leonard G.

AU - Graham, Nicholas A.

AU - Vashisht, Ajay A.

AU - Wohlschlegel, James A.

AU - Graeber, Thomas G.

AU - Karnes, R. Jeffrey

AU - Takhar, Mandeep

AU - Davicioni, Elai

AU - Tomlins, Scott A.

AU - Abate-Shen, Cory

AU - Sharifi, Nima

AU - Witte, Owen N.

AU - Feng, Felix Y.

AU - Knudsen, Karen E.

PY - 2015/7/13

Y1 - 2015/7/13

N2 - Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, invitro and invivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies. Goodwin etal. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.

AB - Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, invitro and invivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies. Goodwin etal. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.

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DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

Abstract

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UN SDGs

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