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Mechanisms of Transcriptional Regulation in Prostate Cancer

By: Vanessa A. Carter, BS
Posted: Monday, April 29, 2024

The development of prostate cancer is associated with transcriptional dysregulation, making it an appropriate model to evaluate molecular mechanisms of dynamic loop formation between target genes in the structure and regulatory elements of the eukaryotic genome that regulate gene expression and cancer progression. To evaluate this further, Michael Zhang, PhD, of The University of Texas at Dallas, and colleagues integrated RNA polymerase II and cohesin with multiple ChIP-sequencing and RNA-sequencing data of prostate cancer cell lines LNCaP, VCaP, DU145, and RWPE1 to perform promoter-centered analysis. Their findings were presented during the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract LB011/11).

“We expect a significant role of super-enhancers in identifying interactions between key oncogenes in prostate cancer, owing to cell-type specific biology,” the authors mentioned. “Overall, this study enhances the knowledge of promoter-centric molecular mechanisms involved in multigene complex formation and coregulated transcription in prostate cancer cell lines.” The next step of the study aims to determine how multigene complexes are formed in prostate cancer for cooperative transcription.

Proportions of RNA polymerase II loops with the co-occupancy of cohesin peaks and RNA polymerase II peaks with cohesin loops were quantified to determine their involvement in transcription regulation. After being validated using simulations, the data supported that RNA polymerase loops were enriched with cohesin peaks. Of note, the opposite was not true, since most cohesin loops created long-range interactions in the form of topologic associating domains.

The investigators identified a quantitative increase in the strength of interaction between loci among RNA polymerase II–mediated interactions but not for cohesin-mediated interactions; they remained stable. However, because of the proposed genetic complexity of the VCaP cell line, the strength of interactions regarding RNA polymerase II and cohesin increased, noted the researchers. When treated with dBET inhibitors, there was no apparent significant difference observed among the strength of interactions between cohesin loops, demonstrating that RNA polymerase II loops were more dynamic, and cohesin loops were more stable.

Disclosure: The study authors reported no conflicts of interest.

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