The Androgen Receptor Does Not Directly Regulate the Transcription of DNA Damage Response Genes.
Mol Cancer Res
; 21(12): 1329-1341, 2023 12 01.
Article
en En
| MEDLINE
| ID: mdl-37698543
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
/
Neoplasias de la Próstata Resistentes a la Castración
Límite:
Humans
/
Male
Idioma:
En
Revista:
Mol Cancer Res
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2023
Tipo del documento:
Article