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

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

doi:10.1016/j.ccell.2015.06.004

Cited by 150 publications

(175 citation statements)

References 60 publications

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“…As such, PRKDC activity in EAC is in line with the genomic rearrangement recently described as a central feature of EAC (8,28). However, PRKDCs is also a central regulator of transcriptional networks, facilitating tumor formation and progression (47). PRKDC may also have clinical relevance as a predictor of sensitivity to chemotherapy, as reported for esophageal SCC (48), and it has been reported as an attractive novel chemotherapeutic target (34).…”

Section: Discussionsupporting

confidence: 52%

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Mååg

Fisher

Levert-Mignon³

et al. 2017

Molecular Cancer Research

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Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE.Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558-69. Ó2017 AACR.

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Section: Discussionsupporting

confidence: 52%

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Mååg

Fisher

Levert-Mignon³

et al. 2017

Molecular Cancer Research

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“…We also observed that the fraction of proteins overlapping with any of the “hallmark” gene sets to be higher when including the phosphoproteomic data, accounting for any potential study bias. These results provide evidence of actionable phosphorylation events in metastatic CRPC, several of which have previously been implicated in this disease including PRKDC, PRKAA2, and AKT (Goodwin et al, 2015; Yu et al, 2015) (Park et al, 2009) while others such as RPS6KA4 and MCM2 represent new drug targets.…”

Section: Resultsmentioning

confidence: 58%

“…S7f ). Indeed, a recent publication evaluated PRKDC function in a panel of prostate cancer cell lines, including 22Rv1, and observed that inhibiting PRKDC activity was effective at delaying metastasis formation after tail vein injection (Goodwin et al, 2015). This result provides evidence that PRKDC activity in the 22Rv1 cell line, as predicted in our models, is essential for development of metastases in vivo and targeting this kinase with a PRKDC selective inhibitor was effective at blocking this process.…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Drake

Paull

Graham

et al. 2016

Cell

197

215

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SUMMARY We used clinical tissue from lethal metastatic castration resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that sheds light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

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“…Furthermore, loss of DNAPK function, either through knockdown or pharmacological inhibition, results in selectively attenuated AR function. This “feed-forward” regulation of AR by DNAPK is likely of clinical significance, as it has been observed that DNAPK is the most highly deregulated kinase in advanced PCa, and is tightly associated with poor disease outcome [69]. The roles of DNAPK in DNA damage resolution as well as AR transcriptional function nominates the kinase as a therapeutic target, which is currently being explored in the clinical setting.…”

Section: Dna Repair Factors As Modulators Of Steroid Receptor Functionmentioning

confidence: 99%

Linking DNA Damage and Hormone Signaling Pathways in Cancer

Schiewer

Knudsen

2016

Trends in Endocrinology & Metabolism

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DNA damage response and repair (DDR) is a tightly controlled process that serves as a barrier to tumorigenesis. Consequently, DDR is frequently altered in human malignancy, and can be exploited for therapeutic gain either through molecularly targeted therapies, or as a consequence of therapeutic agents that induce genotoxic stress. In select tumor types, steroid hormones and cognate receptors serve as major drivers of tumor development/progression, and as such are frequently targets of therapeutic intervention. Recent evidence suggests the existence of crosstalk mechanisms linking the DDR machinery and hormone signaling pathways that cooperate to influence both cancer progression and therapeutic response. These underlying mechanisms and their implications for cancer management will be discussed.

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

Cited by 150 publications

References 60 publications

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Linking DNA Damage and Hormone Signaling Pathways in Cancer

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