|Title||Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Grbesa I, Augello MA, Liu D, McNally DR, Gaffney CD, Huang D, Lin K, Ivenitsky D, Goueli R, Robinson BD, Khani F, Deonarine LD, Blattner M, Elemento O, Davicioni E, Sboner A, Barbieri CE|
|Date Published||2021 Sep 07|
The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.
|Alternate Journal||Cell Rep|
|PubMed Central ID||PMC8477443|
|Grant List||P50 CA211024 / CA / NCI NIH HHS / United States |
R01 CA233650 / CA / NCI NIH HHS / United States
R37 CA215040 / CA / NCI NIH HHS / United States
Andrea Sboner, Ph.D. Brian Robinson, M.D. Francesca Khani, M.D.