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Molecular cancer research : MCR
12 01, 2023;21 (12): 1329-1341.

The Androgen Receptor Does Not Directly Regulate the Transcription of DNA Damage Response Genes.

Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli
Author Information
  1. Sylwia Hasterok: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. ORCID
  2. Thomas G Scott: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia. ORCID
  3. Devin G Roller: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. ORCID
  4. Adam Spencer: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. ORCID
  5. Arun B Dutta: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia. ORCID
  6. Kizhakke M Sathyan: R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut, Farmington, Connecticut. ORCID
  7. Daniel E Frigo: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas. ORCID
  8. Michael J Guertin: R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut, Farmington, Connecticut. ORCID
  9. Daniel Gioeli: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. ORCID
PMID: 37698543 DOI: 10.1158/1541-7786.MCR-23-0358

Abstract

The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in prostate cancer cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at a steady state in asynchronously growing prostate cancer cells.
IMPLICATIONS: Our data indicate that the clinical benefit of combining ADT with RT is not due to direct AR regulation of DDR gene transcription, and that the field needs to consider alternative mechanisms for this clinical benefit.

References

  1. Science. 2015 Jan 23;347(6220):1260419 [PMID: 25613900]
  2. World J Oncol. 2019 Apr;10(2):63-89 [PMID: 31068988]
  3. Nat Commun. 2022 May 13;13(1):2559 [PMID: 35562350]
  4. J Clin Oncol. 2008 May 20;26(15):2497-504 [PMID: 18413638]
  5. EBioMedicine. 2017 Apr;18:83-93 [PMID: 28412251]
  6. Elife. 2017 Aug 10;6: [PMID: 28826504]
  7. Oncogene. 2008 Sep 11;27(40):5348-53 [PMID: 18542058]
  8. Trends Biochem Sci. 2015 Sep;40(9):516-25 [PMID: 26254229]
  9. Endocr Relat Cancer. 2014 Aug;21(4):T131-45 [PMID: 24424504]
  10. Mol Endocrinol. 2010 Dec;24(12):2267-80 [PMID: 20980437]
  11. Cancer Discov. 2013 Nov;3(11):1222-4 [PMID: 24203954]
  12. Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15969-74 [PMID: 17043241]
  13. Lancet. 2002 Jul 13;360(9327):103-6 [PMID: 12126818]
  14. J Biol Chem. 2002 Aug 9;277(32):29304-14 [PMID: 12015328]
  15. J Mol Endocrinol. 2000 Oct;25(2):169-93 [PMID: 11013345]
  16. J Biol Chem. 2012 Mar 9;287(11):8571-83 [PMID: 22275373]
  17. Lancet. 2016 Jan 2;387(10013):70-82 [PMID: 26074382]
  18. Genes Dev. 2019 Oct 1;33(19-20):1441-1455 [PMID: 31467088]
  19. Genes Dev. 2019 Aug 1;33(15-16):960-982 [PMID: 31123063]
  20. Nat Protoc. 2016 Aug;11(8):1455-76 [PMID: 27442863]
  21. Bioinformatics. 2011 Apr 1;27(7):1017-8 [PMID: 21330290]
  22. Sci Signal. 2017 May 23;10(480): [PMID: 28536297]
  23. Br J Radiol. 1953 May;26(305):234-41 [PMID: 13042090]
  24. Lancet Oncol. 2022 Feb;23(2):304-316 [PMID: 35051385]
  25. Sci Rep. 2016 Sep 19;6:33510 [PMID: 27641228]
  26. Genome Res. 2023 Mar;33(3):314-331 [PMID: 36810156]
  27. Elife. 2020 Jun 24;9: [PMID: 32579110]
  28. Nucleic Acids Res. 2019 Jul 2;47(W1):W556-W560 [PMID: 31114875]
  29. Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36 [PMID: 7584402]
  30. Nature. 2020 Feb;578(7793):82-93 [PMID: 32025007]
  31. Cancer Res. 2009 Oct 15;69(20):8133-40 [PMID: 19826053]
  32. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436 [PMID: 31061129]
  33. Nucleic Acids Res. 2017 Jan 25;45(2):619-630 [PMID: 27672034]
  34. Cancers (Basel). 2022 Dec 09;14(24): [PMID: 36551557]
  35. Biotechniques. 2005 Jul;39(1):75-85 [PMID: 16060372]
  36. Cancer Immunol Immunother. 2017 Mar;66(3):281-298 [PMID: 27743027]
  37. Mol Cell Biol. 2004 Mar;24(5):2202-13 [PMID: 14966297]
  38. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52 [PMID: 11483335]
  39. Cancer Res. 2018 Dec 15;78(24):6747-6761 [PMID: 30242113]
  40. Genes Dev. 2018 Sep 1;32(17-18):1105-1140 [PMID: 30181359]
  41. Cell Syst. 2015 Dec 23;1(6):417-425 [PMID: 26771021]
  42. Endocrinology. 2023 Apr 17;164(6): [PMID: 37192413]
  43. Cancer Discov. 2013 Nov;3(11):1245-53 [PMID: 24027196]
  44. Nat Commun. 2021 Dec 15;12(1):7308 [PMID: 34911936]
  45. BMC Cancer. 2018 Oct 10;18(1):960 [PMID: 30305041]
  46. Endocr Relat Cancer. 2014 Oct;21(5):R395-407 [PMID: 25096064]
  47. Cancer Res. 2017 Sep 15;77(18):4745-4754 [PMID: 28754673]
  48. Nat Rev Urol. 2022 Jun;19(6):367-380 [PMID: 35474107]
  49. Nucleic Acids Res. 2015 May 26;43(10):4893-908 [PMID: 25934801]
  50. Cancer Res. 2015 Dec 1;75(23):5093-105 [PMID: 26573794]
  51. Mol Cancer Res. 2013 May;11(5):482-93 [PMID: 23386686]
  52. Nucleic Acids Res. 2019 Jan 8;47(D1):D729-D735 [PMID: 30462313]
  53. Cancer Res. 2023 Mar 15;83(6):906-921 [PMID: 36634207]
  54. Genome Res. 2019 Feb;29(2):293-303 [PMID: 30573452]
  55. Cancer Cell. 2015 Jul 13;28(1):97-113 [PMID: 26175416]
  56. Cancer Discov. 2013 Nov;3(11):1254-71 [PMID: 24027197]
  57. Oncogene. 2021 Mar;40(9):1690-1705 [PMID: 33531625]
  58. Neoplasia. 2008 Feb;10(2):177-88 [PMID: 18283340]
  59. Cancer Discov. 2012 Dec;2(12):1134-49 [PMID: 22993403]
  60. Mol Cancer Ther. 2017 Jul;16(7):1389-1400 [PMID: 28468774]
  61. Nucleic Acids Res. 2017 Apr 20;45(7):3738-3751 [PMID: 28062857]
  62. PLoS One. 2012;7(6):e38950 [PMID: 22761715]
  63. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90 [PMID: 15817329]
  64. Cold Spring Harb Perspect Med. 2019 Jan 2;9(1): [PMID: 29530944]
  65. Mol Cell. 2023 Feb 2;83(3):393-403 [PMID: 36599353]
  66. Nature. 2022 Jun;606(7915):791-796 [PMID: 35322234]
  67. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11256-61 [PMID: 11016951]
  68. J Clin Oncol. 2021 Jan 10;39(2):136-144 [PMID: 33275486]
  69. J Biol Chem. 2005 Mar 18;280(11):10827-33 [PMID: 15640154]
  70. Nucleic Acids Res. 2022 Jan 7;50(D1):D165-D173 [PMID: 34850907]

Grants

  1. R01 CA178338/NCI NIH HHS
  2. R21 CA259716/NCI NIH HHS
  3. R35 GM128635/NIGMS NIH HHS

MeSH Term

Male
Humans
Receptors, Androgen
Prostatic Neoplasms
Androgen Antagonists
Cell Line, Tumor
DNA Damage
Prostatic Neoplasms, Castration-Resistant

Chemicals

Receptors, Androgen
enzalutamide
Androgen Antagonists
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural
Article has an altmetric score of 9

Word Cloud

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