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

Pharmacology

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

134 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

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Publisher Copyright:
© 2015 Elsevier Inc..

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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

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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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.",

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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.

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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.

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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.

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

Abstract

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