BAF57 Deregulation Orchestrates Novel Oncogenic Signaling and Prostate Cancer Progression
Abstract
Prostate cancer (PCa) is one of the leading causes of male mortality in the developed world. The development and progression of PCa is heavily reliant on signaling by the androgen receptor (AR), a ligand-dependent transcription factor. Therefore, AR is the target of current therapies for non-organ confined disease. However, patients relapse approximately 2-3 years after initial treatments using AR antagonists, resulting in recalcitrant disease. This advanced stage of cancer, often termed castration resistant prostate cancer (CRPC), has no effective cure. Therefore, the need for novel, efficacious intervention warrants meticulous investigation of components impinging on AR signaling. The studies described herein define the role of the BAF57 subunit of the SWI/SNF family of chromatin remodeling factors in modulating AR activity with consequences for PCa progression. The first study furnished evidence for the physical interaction of BAF57 with AR and the BAF57 requirement for early AR transcriptional response to ligand. This interaction constituted the basis for the development of a novel peptide inhibitor, termed the BAF57-Inhibitory Peptide (BIPep), to disrupt androgen-dependent, AR-mediated PCa cell proliferation. Targeting the AR-BAF57 interaction could serve as a novel therapeutic approach to block AR activity, since this strategy is directed towards a critical region of AR that is not currently targeted in disease. Moreover, BAF57 upregulation was observed in a small cohort of human PCa specimens. These findings prompted a second study examining the consequences of tumor-derived BAF57 upregulation in clinical samples of high-grade primary and metastatic PCa. Modeling the tumor-derived BAF57 elevation in vitro, followed by microarray analyses, demonstrated the unique upregulation of cytoskeletal remodeler genes such as integrins, with concomitant SWI/SNF anomalies. Integrins are involved in directing pro-migratory, pre-metastatic processes. This study is one of the few to highlight the utility of BAF57 signaling as a potential biomarker of aggressive metastatic disease outcomes. Elucidation of BAF57-governed novel signaling could pave the way for understanding the molecular mechanisms underpinning metastatic PCa and aid the design of putative therapeutic strategies for currently incurable advanced PCa.
Subject Area
Molecular biology|Cellular biology|Oncology
Recommended Citation
Balasubramaniam, Sucharitha, "BAF57 Deregulation Orchestrates Novel Oncogenic Signaling and Prostate Cancer Progression" (2013). ProQuest ETD Collection - Thomas Jefferson University. AAI3566811.
https://jdc.jefferson.edu/dissertations/AAI3566811
