AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer.
| العنوان: | AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer. |
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| المؤلفون: | Sardar S; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA., McNair CM; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA., Ravindranath L; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA., Chand SN; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA., Yuan W; The Institute of Cancer Research, London, United Kingdom., Bogdan D; The Institute of Cancer Research, London, United Kingdom., Welti J; The Institute of Cancer Research, London, United Kingdom., Sharp A; The Institute of Cancer Research, London, United Kingdom.; The Royal Marsden Hospital, London, United Kingdom., Ryan NK; South Australian Immunogenomics Cancer Institute, The University of Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, Australia., Schiewer MJ; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA., DeArment EG; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA., Janas T; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA., Su XA; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Butler LM; South Australian Immunogenomics Cancer Institute, The University of Adelaide, Australia.; South Australian Health and Medical Research Institute, Adelaide, Australia., de Bono JS; The Institute of Cancer Research, London, United Kingdom.; The Royal Marsden Hospital, London, United Kingdom., Frese K; CellCentric Ltd., Cambridge, United Kingdom., Brooks N; CellCentric Ltd., Cambridge, United Kingdom., Pegg N; CellCentric Ltd., Cambridge, United Kingdom., Knudsen KE; The American Cancer Society, Philadelphia, Pennsylvania, 19103, USA., Shafi AA; Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20817, USA.; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, 20817 USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 May 07. Date of Electronic Publication: 2024 May 07. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro , in vivo , and in human prostate cancer (PCa) tumors ex vivo . Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies. Competing Interests: Competing Interests Statement The following are disclosures for authors on this manuscript: Karen E. Knudsen is the CEO of American Cancer Society (ACS). Adam Sharp has received travel support from Sanofi, Roche-Genentech and Nurix, and speaker honoraria from Astellas Pharma and Merck Sharp & Dohme. He has served as an advisor to DE Shaw Research & CHARM Therapeutics and has been the CI/PI of industry-sponsored clinical trials. No disclosures for the other authors. Neil Pegg, Nigel Brooks, and Kris Frese are employees and shareholders of CellCentric Ltd. Neil Pegg is also a board director and the inventor on CCS1477 patents. Johann S de Bono reports grants from CellCentric during the conduct of the study; grants and personal fees from Daiichi Sankyo, AstraZeneca, Pfizer, Bayer Oncology, MSD, Merck Serono, Harpoon, and Genentech/Roche, personal fees from Eisai and Constellation, and grants from Sun Pharma outside the submitted work; in addition, Johann S. de Bono has a patent for Abiraterone licensed and with royalties paid from Janssen. No other disclosures were reported. |
| References: | CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. (PMID: 19474385) Mol Endocrinol. 2007 Aug;21(8):1835-46. (PMID: 17505060) Nat Commun. 2021 Jan 15;12(1):401. (PMID: 33452241) Eur Urol Oncol. 2018 Sep;1(4):325-337. (PMID: 30467556) Cell Death Dis. 2020 Nov 3;11(11):949. (PMID: 33144585) Blood Adv. 2020 Sep 8;4(17):4124-4135. (PMID: 32882003) Br J Cancer. 2002 Mar 18;86(6):899-904. (PMID: 11953821) Clin Cancer Res. 2015 Feb 15;21(4):795-807. (PMID: 25691773) Cell. 1985 Dec;43(3 Pt 2):695-703. (PMID: 3000612) Cell. 2009 Jul 23;138(2):245-56. (PMID: 19632176) Clin Adv Hematol Oncol. 2021 Apr;19(4):228-240. (PMID: 33989272) Cancers (Basel). 2021 Jun 08;13(12):. (PMID: 34201346) BMC Mol Cell Biol. 2020 Jul 20;21(1):55. (PMID: 32690000) Nucleic Acids Res. 2011 Apr;39(8):3116-27. (PMID: 21177654) Nature. 2018 Jun;558(7710):E1. (PMID: 29769713) Clin Cancer Res. 2021 Apr 1;27(7):2087-2099. (PMID: 33495313) Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677) J Urol. 2001 Jun;165(6 Pt 1):1859-62. (PMID: 11371867) Eur J Med Chem. 2021 Jan 1;209:112861. (PMID: 33045661) Pol J Pathol. 2019;70(2):127-133. (PMID: 31556563) Eur Urol. 2021 Apr;79(4):442-445. (PMID: 33012578) Clin Cancer Res. 2009 Aug 1;15(15):4792-8. (PMID: 19638458) Cancer Res. 2002 Oct 15;62(20):5632-6. (PMID: 12384515) Cancer Sci. 2010 Dec;101(12):2538-45. (PMID: 20860770) Mol Oncol. 2018 Sep;12(9):1608-1622. (PMID: 30117261) Acta Pharmacol Sin. 2019 Nov;40(11):1436-1447. (PMID: 31097763) Nucl Recept Signal. 2008 Feb 01;6:e001. (PMID: 18301781) Cancer Gene Ther. 2023 Jan;30(1):124-136. (PMID: 36117234) Cancer Res. 2014 Mar 15;74(6):1870-1880. (PMID: 24480624) Adv Exp Med Biol. 2008;617:535-40. (PMID: 18497079) Biochem Soc Trans. 2001 May;29(Pt 2):196-201. (PMID: 11356153) J Biol Chem. 1998 Nov 27;273(48):31853-9. (PMID: 9822653) PLoS One. 2012;7(12):e52810. (PMID: 23285190) Methods Mol Biol. 2016;1415:245-62. (PMID: 27115637) Genome Biol. 2014;15(12):550. (PMID: 25516281) J Clin Oncol. 2009 Mar 10;27(8):1168-76. (PMID: 19204205) Cancer Metastasis Rev. 2014 Sep;33(2-3):399-411. (PMID: 24425228) Biomed Res Int. 2018 May 15;2018:8168791. (PMID: 29862292) Cancer Discov. 2021 Nov;11(11):2812-2827. (PMID: 34045297) Oncol Rep. 2004 Feb;11(2):453-8. (PMID: 14719083) Nat Rev Cancer. 2015 Dec;15(12):701-11. (PMID: 26563462) Cancer Res. 2004 Dec 15;64(24):9185-92. (PMID: 15604291) Oncology. 2022;100(1):48-59. (PMID: 34781285) Bioorg Med Chem Lett. 2016 Nov 1;26(21):5222-5228. (PMID: 27717544) Prostate. 2022 Jan;82(1):97-106. (PMID: 34633095) PLoS One. 2011 Apr 29;6(4):e19343. (PMID: 21559405) Indian J Urol. 2022 Oct-Dec;38(4):319-320. (PMID: 36568449) Cancer Cell. 2023 Dec 11;41(12):2136-2153.e13. (PMID: 37995682) Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2122-7. (PMID: 9482849) Proc Natl Acad Sci U S A. 2004 May 11;101(19):7386-91. (PMID: 15123817) J Biol Chem. 1999 Jan 22;274(4):1883-6. (PMID: 9890940) Mol Endocrinol. 2014 Jun;28(6):949-64. (PMID: 24801505) Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436. (PMID: 31061129) EMBO Mol Med. 2019 Nov 7;11(11):e10659. (PMID: 31559706) Trends Endocrinol Metab. 2016 Apr;27(4):216-225. (PMID: 26944914) Nature. 2005 Dec 1;438(7068):690-5. (PMID: 16319895) EMBO Mol Med. 2018 Dec;10(12):. (PMID: 30467127) Cancers (Basel). 2021 Oct 28;13(21):. (PMID: 34771580) Med Res Rev. 2019 Sep;39(5):1485-1514. (PMID: 30569509) Endocr Relat Cancer. 2006 Dec;13(4):979-94. (PMID: 17158750) Eur Urol. 2023 Sep;84(3):253-256. (PMID: 37087376) Clin Transl Oncol. 2022 May;24(5):733-741. (PMID: 34743290) Nat Rev Clin Oncol. 2010 Apr;7(4):197-208. (PMID: 20177404) Target Oncol. 2018 Dec;13(6):679-689. (PMID: 30536163) Ann Oncol. 2016 May;27(5):755-7. (PMID: 26865580) Am J Pathol. 2003 Jan;162(1):233-41. (PMID: 12507906) Cell Rep. 2018 Aug 14;24(7):1722-1729. (PMID: 30110629) Cancers (Basel). 2022 Mar 28;14(7):. (PMID: 35406480) Curr Urol Rep. 2012 Apr;13(2):170-8. (PMID: 22373838) J Hematol Oncol. 2015 Nov 13;8:128. (PMID: 26566796) Mol Endocrinol. 2009 Dec;23(12):2038-47. (PMID: 19846536) Curr Urol Rep. 2007 Jan;8(1):53-9. (PMID: 17239317) Cancer Discov. 2013 Nov;3(11):1245-53. (PMID: 24027196) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) J Med Chem. 2024 Feb 22;67(4):2466-2486. (PMID: 38316017) Transcription. 2013 Jan-Feb;4(1):18-23. (PMID: 23131664) Oncogene. 1997 Mar 6;14(9):1047-57. (PMID: 9070653) Cancer Res. 2003 Nov 15;63(22):7638-40. (PMID: 14633682) Pharmacol Ther. 2013 Dec;140(3):223-38. (PMID: 23859952) J Biol Chem. 2012 Feb 3;287(6):4000-13. (PMID: 22174411) Clin Cancer Res. 2020 Jun 1;26(11):2487-2496. (PMID: 32086346) Cancer Res. 2000 Feb 15;60(4):896-900. (PMID: 10706102) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Cancer Treat Res. 2023;186:207-221. (PMID: 37978138) J Pathol. 2024 Jan;262(1):105-120. (PMID: 37850574) JAMA Oncol. 2017 Dec 1;3(12):1663-1672. (PMID: 28494073) Eur Urol Oncol. 2022 Dec;5(6):659-667. (PMID: 35491356) Mol Cancer Ther. 2011 Sep;10(9):1644-55. (PMID: 21709130) Clin Cancer Res. 2018 Sep 1;24(17):4201-4214. (PMID: 29739788) Cancer Discov. 2021 May;11(5):1118-1137. (PMID: 33431496) Semin Oncol. 2013 Jun;40(3):244-58. (PMID: 23806491) Lancet Oncol. 2020 Jan;21(1):162-174. (PMID: 31806540) Cancer Res. 2004 May 1;64(9):3046-51. (PMID: 15126340) Clin Cancer Res. 2024 Mar 15;30(6):1152-1159. (PMID: 38236581) CA Cancer J Clin. 2023 Jan;73(1):17-48. (PMID: 36633525) JAMA Netw Open. 2021 Nov 1;4(11):e2134330. (PMID: 34767021) Cancer Cell. 2015 Jul 13;28(1):97-113. (PMID: 26175416) Cancer Discov. 2013 Nov;3(11):1254-71. (PMID: 24027197) BMC Med. 2022 Jul 22;20(1):237. (PMID: 35864546) Cancer Res. 2017 Oct 15;77(20):5564-5575. (PMID: 28819026) Crit Rev Oncol Hematol. 2020 Mar;147:102888. (PMID: 32018126) JCO Precis Oncol. 2022 Nov;6:e2200460. (PMID: 36446039) Tumour Biol. 2016 Nov;37(11):14335-14340. (PMID: 27612480) Science. 2005 Oct 28;310(5748):644-8. (PMID: 16254181) Biosci Biotechnol Biochem. 2007 Nov;71(11):2712-9. (PMID: 17986787) Med Chem. 2011 Sep;7(5):518-25. (PMID: 22022994) Mod Pathol. 2021 Jun;34(6):1185-1193. (PMID: 33462368) Cancer Res. 2021 Feb 15;81(4):860-872. (PMID: 33361394) Diagnostics (Basel). 2022 Mar 24;12(4):. (PMID: 35453848) Cancer Invest. 2008 Feb;26(1):1-10. (PMID: 18181038) Endocr Relat Cancer. 2016 Dec;23(12):T179-T197. (PMID: 27799360) Nat Rev Clin Oncol. 2010 Jun;7(6):340-7. (PMID: 20440284) Nucleic Acids Res. 2010 Sep;38(16):5396-408. (PMID: 20435671) Cancer Cell. 2017 Oct 9;32(4):474-489.e6. (PMID: 29017058) Methods Enzymol. 2014;546:175-91. (PMID: 25398341) Cancer. 2018 Mar 15;124(6):1216-1224. (PMID: 29266182) Cancer Discov. 2014 Oct;4(10):1126-39. (PMID: 25168287) Target Oncol. 2024 Jan;19(1):1-11. (PMID: 37993604) J Med Chem. 2024 Apr 11;67(7):5351-5372. (PMID: 38530938) Endocr Relat Cancer. 2020 Mar;27(3):187-198. (PMID: 31951590) Urol Oncol. 2016 Aug;34(8):356-67. (PMID: 26706121) |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; P30 CA056036 United States CA NCI NIH HHS; R01 CA182569 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Androgen Receptor (AR); CBP/p300; DNA repair; novel therapeutics; prostate cancer |
| تواريخ الأحداث: | Date Created: 20240520 Latest Revision: 20240524 |
| رمز التحديث: | 20240524 |
| مُعرف محوري في PubMed: | PMC11100730 |
| DOI: | 10.1101/2024.05.07.592966 |
| PMID: | 38766099 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.05.07.592966 |
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