期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 8, 页码 3987-4005出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI134260
关键词
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资金
- NIH Pathway to Independence (PI) Award [R00CA160640]
- National Cancer Institute (NCI), NIH grant [R01CA245294]
- Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award [RP190454]
- US Department of Defense Prostate Cancer Research Program (PCRP) Impact Award [W81XWH-17-1-0675]
- Kidney Cancer Specialized Programs of Research Excellence (SPORE) Career Enhancement Program (CEP) award [P50CA196516]
- UT Southwestern startup funds
- University of Texas at Dallas (UTD) startup fund
- Cecil H. and Ida Green Endowment
- CPRIT [RP180826]
- National Natural Science Foundation of China (NSFC) [31671384, 91329000]
- Movember Foundation
- Prostate Cancer UK
- US Department of Defense
- Prostate Cancer Foundation
- Stand Up To Cancer
- Cancer Research UK
- UK Department of Health through an Experimental Cancer Medicine Centre grant
- Seed Funding Program of Rowan University
- Medical Research Council
- Academy of Medical Sciences, Prostate Cancer UK
- NCI [P30CA016042]
- National Cancer Institute Early Detection Research Network [1U01CA214194-01]
- Prostate Cancer Canada
- Movember Prostate Cancer Canada Rising Star Award
- Canadian Institutes of Health Research (CIHR)
- Terry Fox Research Institute (TFRI) New Investigator Awards
- Wilson Foundation
- Mimi and John Cole Foundation
- MRC [MR/M018318/1] Funding Source: UKRI
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II-associated (RNA Pal II-associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins - CTCF and cohesins - and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant PCa (mCRPC) specimens. we show that AR locus amplification contributes to the transcriptional upregulation of the AR gene by increasing the total number of chromatin interaction modules comprisingthe AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, Z8T816), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes - VR553, FAM57A, and LEMMA. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.
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