DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. 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. Cancer Cell. 2015 Jul 13;28(1):97-113. doi: 10.1016/j.ccell.2015.06.004.
Mechanisms underlying metastatic development remain incompletely defined, and few therapeutic regimens effectively target the metastatic process. Studies here identify DNA-PKcs as a master driver of pro-metastatic signaling and tumor metastasis through transcriptional regulation, thus shifting paradigms with regard to DNA-PKcs activity and illuminating critical functions in human malignancy. Preclinical findings are strongly supported by clinical observations that demonstrate that DNA-PKcs is significantly upregulated in advanced disease and predicts for tumor metastases, recurrence, and poor survival. Moreover, DNA-PKcs was shown to be highly activated in metastatic tumors, independent of DNA damage indicators. These collective findings transform understanding of DNA-PKcs function, establish clinical relevance, and nominate DNA-PKcs as a therapeutic target to suppress metastases.
A hormone-DNA repair circuit governs the response to genotoxic insult. Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, Ma T, Den RB, Dicker AP, Feng FY, Knudsen KE. Cancer Discov. 2013 Nov;3(11):1254-71. doi: 10.1158/2159-8290.CD-13-0108. Epub 2013 Sep 11.
The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease.
Dual roles of PARP-1 promote cancer growth and progression. Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, Liu F, Planck JL, Ravindranathan P, Chinnaiyan AM, McCue P, Gomella LG, Raj GV, Dicker AP, Brody JR, Pascal JM, Centenera MM, Butler LM, Tilley WD, Feng FY, Knudsen KE. Cancer Discov. 2012 Dec;2(12):1134-49. doi: 10.1158/2159-8290.CD-12-0120. Epub 2012 Sep 19.
These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting.