Search

Your search keyword '"Dylgjeri, Emanuela"' showing total 45 results
Start Over Author "Dylgjeri, Emanuela"
45 results on '"Dylgjeri, Emanuela"'

1. DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway

Author

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

Subjects
Prostate Cancer, Urologic Diseases, Genetics, Aging, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, DNA-Activated Protein Kinase, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Heterografts, Humans, Male, Mice, Neoplasm Metastasis, Phenotype, Prostatic Neoplasms, Protein Binding, RNA, Small Interfering, Transcription, Genetic, Wnt Signaling Pathway, Oncology and Carcinogenesis, Oncology & Carcinogenesis
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 long-term 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 of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Published
2019

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

Author

Goodwin, Jonathan F, Kothari, Vishal, Drake, Justin M, Zhao, Shuang, Dylgjeri, Emanuela, Dean, Jeffry L, Schiewer, Matthew J, McNair, Christopher, Jones, Jennifer K, Aytes, Alvaro, Magee, Michael S, Snook, Adam E, Zhu, Ziqi, Den, Robert B, Birbe, Ruth C, Gomella, Leonard G, Graham, Nicholas A, 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, and Knudsen, Karen E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, 2.1 Biological and endogenous factors, Animals, Cell Line, Tumor, DNA-Activated Protein Kinase, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Male, Mice, Molecular Sequence Data, Neoplasm Invasiveness, Neoplasm Transplantation, Nuclear Proteins, Prostatic Neoplasms, Receptors, Androgen, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo 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.

Published
2015

5. Data from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

6. Figure 3 from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

7. Supplementary Figure Legends from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

8. Figure 4 from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

9. Figure 1 from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

10. Figure 2 from Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., primary, McCann, Jennifer J., primary, Yuan, Wei, primary, Laufer, Talya S., primary, Bogdan, Denisa, primary, Gallagher, Lewis, primary, Dylgjeri, Emanuela, primary, Semenova, Galina, primary, Vasilevskaya, Irina A., primary, Schiewer, Matthew J., primary, McNair, Chris M., primary, de Bono, Johann S., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

11. Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Author

McCann, Jennifer J., Vasilevskaya, Irina A., McNair, Christopher, Gallagher, Peter, Neupane, Neermala Poudel, de Leeuw, Renée, Shafi, Ayesha A., Dylgjeri, Emanuela, Mandigo, Amy C., Schiewer, Matthew J., and Knudsen, Karen E.

Abstract

The tumor suppressor gene TP53is the most frequently mutated gene in numerous cancer types, including prostate cancer (PCa). Specifically, missense mutations in TP53are selectively enriched in PCa, and cluster to particular “hot spots” in the p53 DNA binding domain with mutation at the R273 residue occurring most frequently. While this residue is similarly mutated to R273C-p53 or R273H-p53 in all cancer types examined, in PCa selective enrichment of R273C-p53 is observed. Importantly, examination of clinical datasets indicated that TP53heterozygosity can either be maintained or loss of heterozygosity (LOH) occurs. Thus, to mimic tumor-associated mutant p53, R273C-p53 and R273H-p53 isogenic PCa models were developed in the presence or absence of wild-type p53. In the absence of wild-type p53, both R273C-p53 and R273H-p53 exhibited similar loss of DNA binding, transcriptional profiles, and loss of canonical tumor suppressor functions associated with wild-type p53. In the presence of wild-type p53 expression, both R273C-p53 and R273H-p53 supported canonical p53 target gene expression yet elicited distinct cistromic and transcriptional profiles when compared to each other. Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.

Published
2024
Full Text
View/download PDF

12. Supplementary Table from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, primary, Kothari, Vishal, primary, Shafi, Ayesha A., primary, Semenova, Galina, primary, Gallagher, Peter T., primary, Guan, Yi F., primary, Pang, Angel, primary, Goodwin, Jonathan F., primary, Irani, Swati, primary, McCann, Jennifer J., primary, Mandigo, Amy C., primary, Chand, Saswati, primary, McNair, Christopher M., primary, Vasilevskaya, Irina, primary, Schiewer, Matthew J., primary, Lallas, Costas D., primary, McCue, Peter A., primary, Gomella, Leonard G., primary, Seifert, Erin L., primary, Carroll, Jason S., primary, Butler, Lisa M., primary, Holst, Jeff, primary, Kelly, William K., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

13. Supplementary Data from USP22 Functions as an Oncogenic Driver in Prostate Cancer by Regulating Cell Proliferation and DNA Repair

Author

McCann, Jennifer J., primary, Vasilevskaya, Irina A., primary, Poudel Neupane, Neermala, primary, Shafi, Ayesha A., primary, McNair, Christopher, primary, Dylgjeri, Emanuela, primary, Mandigo, Amy C., primary, Schiewer, Matthew J., primary, Schrecengost, Randy S., primary, Gallagher, Peter, primary, Stanek, Timothy J., primary, McMahon, Steven B., primary, Berman-Booty, Lisa D., primary, Ostrander, William F., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

14. Supplementary Figure from A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, primary, Kothari, Vishal, primary, Shafi, Ayesha A., primary, Semenova, Galina, primary, Gallagher, Peter T., primary, Guan, Yi F., primary, Pang, Angel, primary, Goodwin, Jonathan F., primary, Irani, Swati, primary, McCann, Jennifer J., primary, Mandigo, Amy C., primary, Chand, Saswati, primary, McNair, Christopher M., primary, Vasilevskaya, Irina, primary, Schiewer, Matthew J., primary, Lallas, Costas D., primary, McCue, Peter A., primary, Gomella, Leonard G., primary, Seifert, Erin L., primary, Carroll, Jason S., primary, Butler, Lisa M., primary, Holst, Jeff, primary, Kelly, William K., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

15. Supplementary Data from Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies

Author

Dylgjeri, Emanuela, primary, McNair, Christopher, primary, Goodwin, Jonathan F., primary, Raymon, Heather K., primary, McCue, Peter A., primary, Shafi, Ayesha A., primary, Leiby, Benjamin E., primary, de Leeuw, Renée, primary, Kothari, Vishal, primary, McCann, Jennifer J., primary, Mandigo, Amy C., primary, Chand, Saswati N., primary, Schiewer, Matthew J., primary, Brand, Lucas J., primary, Vasilevskaya, Irina, primary, Gordon, Nicolas, primary, Laufer, Talya S., primary, Gomella, Leonard G., primary, Lallas, Costas D., primary, Trabulsi, Edouard J., primary, Feng, Felix Y., primary, Filvaroff, Ellen H., primary, Hege, Kristin, primary, Rathkopf, Dana, primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

16. Supplementary Tables from Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies

Author

Dylgjeri, Emanuela, primary, McNair, Christopher, primary, Goodwin, Jonathan F., primary, Raymon, Heather K., primary, McCue, Peter A., primary, Shafi, Ayesha A., primary, Leiby, Benjamin E., primary, de Leeuw, Renée, primary, Kothari, Vishal, primary, McCann, Jennifer J., primary, Mandigo, Amy C., primary, Chand, Saswati N., primary, Schiewer, Matthew J., primary, Brand, Lucas J., primary, Vasilevskaya, Irina, primary, Gordon, Nicolas, primary, Laufer, Talya S., primary, Gomella, Leonard G., primary, Lallas, Costas D., primary, Trabulsi, Edouard J., primary, Feng, Felix Y., primary, Filvaroff, Ellen H., primary, Hege, Kristin, primary, Rathkopf, Dana, primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

17. Data from Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies

Author

Dylgjeri, Emanuela, primary, McNair, Christopher, primary, Goodwin, Jonathan F., primary, Raymon, Heather K., primary, McCue, Peter A., primary, Shafi, Ayesha A., primary, Leiby, Benjamin E., primary, de Leeuw, Renée, primary, Kothari, Vishal, primary, McCann, Jennifer J., primary, Mandigo, Amy C., primary, Chand, Saswati N., primary, Schiewer, Matthew J., primary, Brand, Lucas J., primary, Vasilevskaya, Irina, primary, Gordon, Nicolas, primary, Laufer, Talya S., primary, Gomella, Leonard G., primary, Lallas, Costas D., primary, Trabulsi, Edouard J., primary, Feng, Felix Y., primary, Filvaroff, Ellen H., primary, Hege, Kristin, primary, Rathkopf, Dana, primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

18. Data from USP22 Functions as an Oncogenic Driver in Prostate Cancer by Regulating Cell Proliferation and DNA Repair

Author

McCann, Jennifer J., primary, Vasilevskaya, Irina A., primary, Poudel Neupane, Neermala, primary, Shafi, Ayesha A., primary, McNair, Christopher, primary, Dylgjeri, Emanuela, primary, Mandigo, Amy C., primary, Schiewer, Matthew J., primary, Schrecengost, Randy S., primary, Gallagher, Peter, primary, Stanek, Timothy J., primary, McMahon, Steven B., primary, Berman-Booty, Lisa D., primary, Ostrander, William F., primary, and Knudsen, Karen E., primary

Published
2023
Full Text
View/download PDF

19. PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer

Author

Gordon, Nicolas, primary, Gallagher, Peter T, additional, Neupane, Neermala Poudel, additional, Mandigo, Amy C, additional, McCann, Jennifer K, additional, Dylgjeri, Emanuela, additional, Vasilevskaya, Irina, additional, McNair, Christopher, additional, Paller, Channing J, additional, Kelly, Wm Kevin, additional, Knudsen, Karen E, additional, Shafi, Ayesha A, additional, and Schiewer, Matthew J, additional

Published
2023
Full Text
View/download PDF

20. PARP‐1 regulates DNA repair factor availability

Author

Schiewer, Matthew J, Mandigo, Amy C, Gordon, Nicolas, Huang, Fangjin, Gaur, Sanchaika, de Leeuw, Renée, Zhao, Shuang G, Evans, Joseph, Han, Sumin, Parsons, Theodore, Birbe, Ruth, McCue, Peter, McNair, Christopher, Chand, Saswati N, Cendon‐Florez, Ylenia, Gallagher, Peter, McCann, Jennifer J, Poudel Neupane, Neermala, Shafi, Ayesha A, Dylgjeri, Emanuela, Brand, Lucas J, Visakorpi, Tapio, Raj, Ganesh V, Lallas, Costas D, Trabulsi, Edouard J, Gomella, Leonard G, Dicker, Adam P, Kelly, Wm. Kevin, Leiby, Benjamin E, Knudsen, Beatrice, Feng, Felix Y, and Knudsen, Karen E

Published
2018
Full Text
View/download PDF

21. Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., Shafi, Ayesha A, McCann, Jennifer J, Yuan, Wei, Laufer, Talya, Bogdan, Denisa, Gallagher, Lewis, Dylgjeri, Emanuela, Semenova, Galina, Vasilevskaya, Irina A, Schiewer, M J, McNair, Chris M, de Bono, Johann S, Knudsen, Karen E, Mandigo, Amy C., Shafi, Ayesha A, McCann, Jennifer J, Yuan, Wei, Laufer, Talya, Bogdan, Denisa, Gallagher, Lewis, Dylgjeri, Emanuela, Semenova, Galina, Vasilevskaya, Irina A, Schiewer, M J, McNair, Chris M, de Bono, Johann S, and Knudsen, Karen E

Abstract

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. SIGNIFICANCE: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease.

Published
2022

22. DNA-PKcs: A Targetable Protumorigenic Protein Kinase.

Author

Dylgjeri, Emanuela, Knudsen, Karen E, Dylgjeri, Emanuela, and Knudsen, Karen E

Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a pleiotropic protein kinase that plays critical roles in cellular processes fundamental to cancer. DNA-PKcs expression and activity are frequently deregulated in multiple hematologic and solid tumors and have been tightly linked to poor outcome. Given the potentially influential role of DNA-PKcs in cancer development and progression, therapeutic targeting of this kinase is being tested in preclinical and clinical settings. This review summarizes the latest advances in the field, providing a comprehensive discussion of DNA-PKcs functions in cancer and an update on the clinical assessment of DNA-PK inhibitors in cancer therapy.

Published
2022

23. A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, Kothari, Vishal, Shafi, Ayesha A, Semenova, Galina, Gallagher, Peter T, Guan, Yi Fang, Pang, Angel, Goodwin, Jonathan F, Irani, Swati, McCann, Jennifer J, Mandigo, Amy C, Chand, Saswati, McNair, Christopher M, Vasilevskaya, Irina, Schiewer, Matthew J, Lallas, Costas D, McCue, Peter A, Gomella, Leonard G, Seifert, Erin L, Carroll, Jason S, Butler, Lisa M, Holst, Jeff, Kelly, William K, Knudsen, Karen E, Carroll, Jason [0000-0003-3643-0080], and Apollo - University of Cambridge Repository

Subjects
Male, Proteomics, Prostatic Neoplasms, Castration-Resistant, Pyruvate Kinase, Humans, DNA, DNA-Activated Protein Kinase, Glycolysis
Abstract

PURPOSE: DNA-dependent kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer (PCa), and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. While DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. EXPERIMENTAL DESIGN: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacological and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). RESULTS: Key findings reveal: i) the first-in-field DNA-PK protein-protein interactome; ii) numerous DNA-PK novel partners involved in glycolysis, iii) DNA-PK interacts with, phosphorylates (in vitro) and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2, iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate, v) DNA-PK regulates glycolysis in vitro, in vivo and ex vivo, and vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. CONCLUSIONS: Findings herein unveil novel DNA-PK partners, substrates, and function in PCa. The role of DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.

Published
2022
Full Text
View/download PDF

24. A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, primary, Kothari, Vishal, additional, Shafi, Ayesha A., additional, Semenova, Galina, additional, Gallagher, Peter T., additional, Guan, Yi F., additional, Pang, Angel, additional, Goodwin, Jonathan F., additional, Irani, Swati, additional, McCann, Jennifer J., additional, Mandigo, Amy C., additional, Chand, Saswati, additional, McNair, Christopher M., additional, Vasilevskaya, Irina, additional, Schiewer, Matthew J., additional, Lallas, Costas D., additional, McCue, Peter A., additional, Gomella, Leonard G., additional, Seifert, Erin L., additional, Carroll, Jason S., additional, Butler, Lisa M., additional, Holst, Jeff, additional, Kelly, William K., additional, and Knudsen, Karen E., additional

Published
2022
Full Text
View/download PDF

26. Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Author

McCann, Jennifer J., primary, Vasilevskaya, Irina A., additional, McNair, Christopher, additional, Gallagher, Peter, additional, Neupane, Neermala Poudel, additional, de Leeuw, Renée, additional, Shafi, Ayesha A., additional, Dylgjeri, Emanuela, additional, Mandigo, Amy C., additional, Schiewer, Matthew J., additional, and Knudsen, Karen E., additional

Published
2021
Full Text
View/download PDF

27. Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., additional, McCann, Jennifer J., additional, Yuan, Wei, additional, Laufer, Talya S., additional, Bogdan, Denisa, additional, Gallagher, Lewis, additional, Dylgjeri, Emanuela, additional, Semenova, Galina, additional, Vasilevskaya, Irina A., additional, Schiewer, Matthew J., additional, McNair, Chris M., additional, de Bono, Johann S., additional, and Knudsen, Karen E., additional

Published
2021
Full Text
View/download PDF

28. DNA-PKcs: Novel Roles and Therapeutic Targeting in Prostate Cancer

Author

Dylgjeri, Emanuela and Dylgjeri, Emanuela

Abstract

Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related deaths in men in the Unites States. While early-stage disease is treatable, the advanced stage of disease termed castration resistant prostate cancer (CRPC) remains fatal. The androgen receptor (AR) has been identified as a driver of the disease at all stages, thus first line of therapy is directed toward control of AR activity and AR-mediated processes. Nevertheless, AR-directed therapies are not durable. Significant work has been done to identify AR partners and targets that promote proliferation and metastasis, in order to provide therapeutic targeting downstream of AR. DNA-dependent protein kinase catalytic subunit (DNA-PKcs, referred as DNA-PK herein) is a pleiotropic protein well known for its role in DNA repair through non-homologous end joining (NHEJ). AR was found to promote DNA repair through regulation of DNA-PK expression and activity upon DNA damage, while activated DNA-PK transcriptionally regulates pro-metastatic gene networks to promote aggressive disease. Furthermore, DNA-PK has been identified as the most deregulated kinase in men with metastatic CRPC and can independently predict for poor outcome in patients with high-risk disease. Consequently, DNA-PK has been nominated as a therapeutic target and DNA-PK inhibitors are in clinical development. While DNA-PK is well known for its role in NHEJ, delineating the molecular mechanisms of DNA-PK pro-tumorigenic functions beyond DNA repair will allow for improved management and treatment of CRPC patients. The studies herein utilized unbiased proteomic and metabolomic approaches to identify a novel role of DNA-PK in regulation of glycolysis through interaction, phosphorylation, and modulation of enzymatic activity of glycolysis protein partners ALDOA and PKM2. The effects of DNA-PK in metabolic regulation were tested in in vitro, in vivo, and patient tumor samples. These studies al

Published
2021

29. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair.

Author

Shafi, Ayesha A, McNair, Chris M, McCann, Jennifer J, Alshalalfa, Mohammed, Shostak, Anton, Severson, Tesa M, Zhu, Yanyun, Bergman, Andre, Gordon, Nicolas, Mandigo, Amy C, Chand, Saswati N, Gallagher, Peter, Dylgjeri, Emanuela, Laufer, Talya S, Vasilevskaya, Irina A, Schiewer, Matthew J, Brunner, Michael, Feng, Felix Y, Zwart, Wilbert, Knudsen, Karen E, Shafi, Ayesha A, McNair, Chris M, McCann, Jennifer J, Alshalalfa, Mohammed, Shostak, Anton, Severson, Tesa M, Zhu, Yanyun, Bergman, Andre, Gordon, Nicolas, Mandigo, Amy C, Chand, Saswati N, Gallagher, Peter, Dylgjeri, Emanuela, Laufer, Talya S, Vasilevskaya, Irina A, Schiewer, Matthew J, Brunner, Michael, Feng, Felix Y, Zwart, Wilbert, and Knudsen, Karen E

Abstract

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.

Published
2021

30. RB/E2F1 as a Master Regulator of Cancer Cell Metabolism in Advanced Disease

Author

Mandigo, Amy C., primary, Yuan, Wei, additional, Xu, Kexin, additional, Gallagher, Peter, additional, Pang, Angel, additional, Guan, Yi Fang, additional, Shafi, Ayesha A., additional, Thangavel, Chellappagounder, additional, Sheehan, Beshara, additional, Bogdan, Denisa, additional, Paschalis, Alec, additional, McCann, Jennifer J., additional, Laufer, Talya S., additional, Gordon, Nicolas, additional, Vasilevskaya, Irina A., additional, Dylgjeri, Emanuela, additional, Chand, Saswati N., additional, Schiewer, Matthew J., additional, Domingo-Domenech, Josep, additional, Den, Robert B., additional, Holst, Jeff, additional, McCue, Peter A., additional, de Bono, Johann S., additional, McNair, Christopher, additional, and Knudsen, Karen E., additional

Published
2021
Full Text
View/download PDF

31. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

Author

Shafi, Ayesha A., primary, McNair, Chris M., additional, McCann, Jennifer J., additional, Alshalalfa, Mohammed, additional, Shostak, Anton, additional, Severson, Tesa M., additional, Zhu, Yanyun, additional, Bergman, Andre, additional, Gordon, Nicolas, additional, Mandigo, Amy C., additional, Chand, Saswati N., additional, Gallagher, Peter, additional, Dylgjeri, Emanuela, additional, Laufer, Talya S., additional, Vasilevskaya, Irina A., additional, Schiewer, Matthew J., additional, Brunner, Michael, additional, Feng, Felix Y., additional, Zwart, Wilbert, additional, and Knudsen, Karen E., additional

Published
2021
Full Text
View/download PDF

32. USP22 Functions as an Oncogenic Driver in Prostate Cancer by Regulating Cell Proliferation and DNA Repair

Author

McCann, Jennifer J., primary, Vasilevskaya, Irina A., additional, Poudel Neupane, Neermala, additional, Shafi, Ayesha A., additional, McNair, Christopher, additional, Dylgjeri, Emanuela, additional, Mandigo, Amy C., additional, Schiewer, Matthew J., additional, Schrecengost, Randy S., additional, Gallagher, Peter, additional, Stanek, Timothy J., additional, McMahon, Steven B., additional, Berman-Booty, Lisa D., additional, Ostrander, William F., additional, and Knudsen, Karen E., additional

Published
2020
Full Text
View/download PDF

33. Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies

Author

Dylgjeri, Emanuela, primary, McNair, Christopher, additional, Goodwin, Jonathan F., additional, Raymon, Heather K., additional, McCue, Peter A., additional, Shafi, Ayesha A., additional, Leiby, Benjamin E., additional, de Leeuw, Renée, additional, Kothari, Vishal, additional, McCann, Jennifer J., additional, Mandigo, Amy C., additional, Chand, Saswati N., additional, Schiewer, Matthew J., additional, Brand, Lucas J., additional, Vasilevskaya, Irina, additional, Gordon, Nicolas, additional, Laufer, Talya S., additional, Gomella, Leonard G., additional, Lallas, Costas D., additional, Trabulsi, Edouard J., additional, Feng, Felix Y., additional, Filvaroff, Ellen H., additional, Hege, Kristin, additional, Rathkopf, Dana, additional, and Knudsen, Karen E., additional

Published
2019
Full Text
View/download PDF

35. Abstract 112: Patient derived models reveal impact of the tumor microenvironment on therapeutic response

Author

Shafi, Ayesha A., primary, Schiewer, Matthew J., additional, Leeuw, Renée de, additional, Dylgjeri, Emanuela, additional, McCue, Peter A., additional, Shah, Neelima, additional, Gomella, Leonard, additional, Lallas, Costas, additional, Trabulsi, Edouard, additional, Centerera, Margaret, additional, Hickey, Theresa, additional, Butler, Lisa, additional, Raj, Ganesh, additional, Tilley, Wayne, additional, Cukierman, Edna, additional, and Knudsen, Karen E., additional

Published
2019
Full Text
View/download PDF

36. Synergistic effects of the PARP inhibitor olaparib and pharmacological ascorbate in castration-resistant prostate cancer.

Author

Gordon, Nicolas, primary, Schiewer, Matthew Joseph, additional, Gallagher, Peter, additional, Mandigo, Amy C, additional, Dylgjeri, Emanuela, additional, McNair, Christopher, additional, De Leeuw, Renee, additional, Jones, Jennifer K, additional, Neupane, Neermala Poudel, additional, Shafi, Ayesha A, additional, Brand, Lucas, additional, Kelly, William Kevin, additional, and Knudsen, Karen E., additional

Published
2019
Full Text
View/download PDF

37. PARP-1 regulates DNA repair factor availability.

Author

Schiewer, M J, Mandigo, Amy C., Gordon, Nicolas, Huang, Fangjin, Gaur, Sanchaika, de Leeuw, Renée, Zhao, Shuang G, Evans, Joseph, Han, Sumin, Parsons, Theodore, Birbe, Ruth, McCue, Peter, McNair, Christopher, Chand, Saswati N., Cendon-Florez, Ylenia, Gallagher, Peter, McCann, Jennifer J, Poudel Neupane, Neermala, Shafi, Ayesha A, Dylgjeri, Emanuela, Brand, Lucas J, Visakorpi, Tapio, Raj, Ganesh V, Lallas, Costas D, Trabulsi, Edouard J, Gomella, Leonard G, Dicker, Adam, MD, PhD, Kelly, William Kevin, Leiby, Benjamin E, Knudsen, Beatrice, Feng, Felix Y, Knudsen, Karen E, Schiewer, M J, Mandigo, Amy C., Gordon, Nicolas, Huang, Fangjin, Gaur, Sanchaika, de Leeuw, Renée, Zhao, Shuang G, Evans, Joseph, Han, Sumin, Parsons, Theodore, Birbe, Ruth, McCue, Peter, McNair, Christopher, Chand, Saswati N., Cendon-Florez, Ylenia, Gallagher, Peter, McCann, Jennifer J, Poudel Neupane, Neermala, Shafi, Ayesha A, Dylgjeri, Emanuela, Brand, Lucas J, Visakorpi, Tapio, Raj, Ganesh V, Lallas, Costas D, Trabulsi, Edouard J, Gomella, Leonard G, Dicker, Adam, MD, PhD, Kelly, William Kevin, Leiby, Benjamin E, Knudsen, Beatrice, Feng, Felix Y, and Knudsen, Karen E

Abstract

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting.

Published
2018

41. Abstract 1860: DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis

Author

Goodwin, Jonathan F., primary, Kothari, Vishal, additional, Drake, Justin M., additional, Zhao, Shuang, additional, Dylgjeri, Emanuela, additional, Dean, Jeffry L., additional, Schiewer, Matthew J., additional, McNair, Christopher, additional, Magee, Michael S., additional, Den, Robert B., additional, Zhu, Ziqi, additional, Graham, Nicholas A., additional, Vashisht, Ajay A., additional, Wohlschlegel, James A., additional, Graeber, Thomas G., additional, Karnes, R Jeffrey, additional, Takhar, Mandeep, additional, Davicioni, Elai, additional, Tomlins, Scott A., additional, Sharifi, Nima, additional, Witte, Owen N., additional, Feng, Felix Y., additional, and Knudsen, Karen E., additional

Published
2015
Full Text
View/download PDF

43. PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer.

Author

Gordon N, Gallagher PT, Neupane NP, Mandigo AC, McCann JK, Dylgjeri E, Vasilevskaya I, McNair C, Paller CJ, Kelly WK, Knudsen KE, Shafi AA, and Schiewer MJ

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. While organ-confined disease has reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the CRPC population as a whole. The administration of ascorbate, more commonly known as ascorbic acid or Vitamin C, has proved lethal to and highly selective for a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anti-cancer effects. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors, by inhibiting DNA damage repair, would augment the toxicity of ascorbate., Results: Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and non-castrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control., Conclusions: These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo . These findings nominate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.

Published
2023
Full Text
View/download PDF

44. DNA-PKcs: A Targetable Protumorigenic Protein Kinase.

Author

Dylgjeri E and Knudsen KE

Subjects
Animals, Clinical Trials as Topic, DNA-Activated Protein Kinase antagonists & inhibitors, DNA-Activated Protein Kinase metabolism, Humans, Neoplasms drug therapy, Neoplasms enzymology, Protein Kinase Inhibitors therapeutic use, Substrate Specificity, Tumor Microenvironment drug effects, Tumor Microenvironment genetics, DNA-Activated Protein Kinase genetics, Energy Metabolism genetics, Gene Expression Regulation, Neoplastic, Immunity genetics, Neoplasms genetics, Protein Biosynthesis genetics
Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a pleiotropic protein kinase that plays critical roles in cellular processes fundamental to cancer. DNA-PKcs expression and activity are frequently deregulated in multiple hematologic and solid tumors and have been tightly linked to poor outcome. Given the potentially influential role of DNA-PKcs in cancer development and progression, therapeutic targeting of this kinase is being tested in preclinical and clinical settings. This review summarizes the latest advances in the field, providing a comprehensive discussion of DNA-PKcs functions in cancer and an update on the clinical assessment of DNA-PK inhibitors in cancer therapy., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2022
Full Text
View/download PDF

45. Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer.

Author

Mandigo AC, Shafi AA, McCann JJ, Yuan W, Laufer TS, Bogdan D, Gallagher L, Dylgjeri E, Semenova G, Vasilevskaya IA, Schiewer MJ, McNair CM, de Bono JS, and Knudsen KE

Subjects
Apoptosis genetics, Binding Sites, Cell Line, Tumor, Cell Survival genetics, Cohort Studies, E2F1 Transcription Factor genetics, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Male, Oncogene Proteins genetics, Oncogenes, Prostatic Neoplasms pathology, Protein Binding genetics, Retinoblastoma Binding Proteins genetics, Transfection, Ubiquitin-Protein Ligases genetics, Carcinogenesis genetics, E2F1 Transcription Factor metabolism, Oncogene Proteins metabolism, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism, Retinoblastoma Binding Proteins metabolism, Signal Transduction genetics, Ubiquitin-Protein Ligases metabolism
Abstract

The retinoblastoma tumor suppressor (RB) is a critical regulator of E2F-dependent transcription, controlling a multitude of protumorigenic networks including but not limited to cell-cycle control. Here, genome-wide assessment of E2F1 function after RB loss in isogenic models of prostate cancer revealed unexpected repositioning and cooperation with oncogenic transcription factors, including the major driver of disease progression, the androgen receptor (AR). Further investigation revealed that observed AR/E2F1 cooperation elicited novel transcriptional networks that promote cancer phenotypes, especially as related to evasion of cell death. These observations were reflected in assessment of human disease, indicating the clinical relevance of the AR/E2F1 cooperome in prostate cancer. Together, these studies reveal new mechanisms by which RB loss induces cancer progression and highlight the importance of understanding the targets of E2F1 function. SIGNIFICANCE: This study identifies that RB loss in prostate cancer drives cooperation between AR and E2F1 as coregulators of transcription, which is linked to the progression of advanced disease., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results