MP20-01 PROTEIN KINASE D1 (PrKD) PROTECTS AGAINST DNA DAMAGE BY INCREASING Α-CATENIN LEVELS THROUGH PUTATIVE SERINE681 AND 685 PHOSPHORYLATION OF CYCLIN DEPENDENT KINASE 12 (CDK12) IN PROSTATE CANCER (PC)

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP20-01 PROTEIN KINASE D1 (PrKD) PROTECTS AGAINST DNA DAMAGE BY INCREASING Α-CATENIN LEVELS THROUGH PUTATIVE SERINE681 AND 685 PHOSPHORYLATION OF CYCLIN DEPENDENT KINASE 12 (CDK12) IN PROSTATE CANCER (PC) Sanjeev Shukla, Teruko Osumi, Mohammed Al-Toubat, Carlos Riveros, Allison H. Feibus, Ahmed El-shafie, Adam M. Kase, John A. Copland, Joachim L. Petit, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, and K. C. Balaji Sanjeev ShuklaSanjeev Shukla More articles by this author , Teruko OsumiTeruko Osumi More articles by this author , Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Carlos RiverosCarlos Riveros More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , Ahmed El-shafieAhmed El-shafie More articles by this author , Adam M. KaseAdam M. Kase More articles by this author , John A. CoplandJohn A. Copland More articles by this author , Joachim L. PetitJoachim L. Petit More articles by this author , Nathalie MeuriceNathalie Meurice More articles by this author , Justyna GlebaJustyna Gleba More articles by this author , Jonathan Chardon-RoblesJonathan Chardon-Robles More articles by this author , and K. C. BalajiK. C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PrKD is protective of DNA damage in PC and loss of PrKD leading to increased genomic instability is a novel potential mechanism. CDK12 mutated PC is now recognized as a distinct aggressive variant associated with genomic instability. We explored whether PrKD influences DNA damage through CDK12. METHODS: The DNA damage and protein levels studied by COMET assay and western blot respectively and validated the findings in human PC samples by querying cBioPortal gene expression. RESULTS: PrKD abrogated etoposide induced DNA damage in castration insensitive C4-2 PC cells. PrKD is a membrane bound protein that phosphorylates proteins in cell adherens junction including β-catenin. As PrKD is the only known kinase to phosphorylate T120 in β-catenin, mutation of T120 leads to nuclear translocation of transcriptionally active β-catenin playing a role in DNA damage, uncouples the binding of β- to α-catenin, which translocates to the nucleus and influences β-catenin. PrKD increased the expression of α-catenin, which was attenuated by CDK12 wild type and double non-phosphorylated mutants of PrKD putative phosphorylation sites; serine (s) 681 and 685 but not as much by s681 mutant. PrKD suppressed the substrate phosphorylation of γH2AX s139 by CDK12 s681 and s681/s685 non-phosphorylated mutant compared to wild type, which links PrKD substrate phosphorylation of CDK12 to DNA damage. Query of cBioPortal for concurrent PrKD1 and CDK12 mutations in PC with characteristic gene signature of DNA damage repair (DDR) revealed the highest concordance of PrKD1 and CDK12 mutations in patients with BRAC2 mutations and the DDR genes expression were not significantly different between patients with PrKD1 and CDK12 mutated patient except BRAC1 expression (rarely mutated in PC) suggesting that PrKD1 and CDK12 could be involved in the same signaling pathway (Figure 1). CONCLUSIONS: The study provides a validated mechanistic basis for the novel protective role of PrKD in DNA damage, which has potential implications in PC therapeutics linked to DNA damage. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e275 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanjeev Shukla More articles by this author Teruko Osumi More articles by this author Mohammed Al-Toubat More articles by this author Carlos Riveros More articles by this author Allison H. Feibus More articles by this author Ahmed El-shafie More articles by this author Adam M. Kase More articles by this author John A. Copland More articles by this author Joachim L. Petit More articles by this author Nathalie Meurice More articles by this author Justyna Gleba More articles by this author Jonathan Chardon-Robles More articles by this author K. C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...