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Author
Title BAF57 MODULATION OF ANDROGEN RECEPTOR ACTION AND PROSTATE CANCER PROGRESSION
URL
Publication Date
Degree PhD
Discipline/Department Medicine : Cell and Molecular Biology
Degree Level doctoral
University/Publisher University of Cincinnati
Abstract Prostate cancer relies on androgens for growth and survival. Androgens elicit their function primarily through the androgen receptor (AR), a transcription factor that is required for the development and progression of prostate cancer. Therefore, current treatment options for disseminated disease are aimed at either inhibiting androgen synthesis or preventing activation of the receptor. These treatment options are initially effective; however, recurrent disease ultimately arises within two to three years that typically present as therapy resistant. From this, it is obvious that more effective means of targeting this pathway are necessary to treat prostate cancer. The present study exploited a specific aspect of the AR activation pathway and uncovered a novel means for potentially targeting AR action and subsequent prostate cancer proliferation. The SWI/SNF chromatin remodeling complex is one such necessary component involved in mediating AR activation. Specifically, the BRM core ATPase was demonstrated to exhibit a preferential response to activating AR target genes which was dependent on promoter context. Subsequent studies identified the BAF57 subunit of the SWI/SNF complex as the primary interacting AR subunit, thus indicating a possible role in complex recruitment to AR target DNA. BAF57 proved to be critical for AR mediated transcriptional activation, AR enhanced coactivator activation, and prostate cancer proliferation. Based on these findings, the potential for targeting BAF57 as a prostate cancer therapeutic option was examined. First, expression of BAF57 was verified in human prostate tissue specimens, with possible enhanced expression observed in metastatic samples. Subsequent molecular analyses determined that the primary region of interaction occurred between the DBD/hinge region of AR and the proline-rich/HMG domain of BAF57. The N-terminal binding region of BAF57 was then shown to reduce AR recruitment to AR target genes, inhibit AR target gene activity, and decrease prostate cancer cell proliferation. Together, the data herein establish the SWI/SNF chromatin remodeling complex, specifically BAF57, as a valid target for the treatment of prostate cancer.
Subjects/Keywords Biology, Molecular; prostate cancer; androgen receptor; BAF57; SWI/SNF
Contributors Knudsen, Dr. Karen (Advisor)
Language en
Rights unrestricted ; This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
Country of Publication us
Format application/pdf
Record ID oai:etd.ohiolink.edu:ucin1198854849
Repository ohiolink
Date Indexed 2021-01-29
Grantor University of Cincinnati

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BAF57 Modulation of Androgen Receptor Action and Prostate Cancer Progression A dissertation submitted to the Division of Research and Advanced Studies at the University of Cincinnati in partial fulfillment of the requirements for the degree of…

…exhibit a preferential response to activating AR target genes which was dependent on promoter context. Subsequent studies identified the BAF57 subunit of the SWI/SNF complex as the primary interacting AR subunit, thus indicating a possible role in complex…

…recruitment to AR target DNA. BAF57 proved to be critical for AR mediated transcriptional activation, AR enhanced coactivator activation, and prostate cancer proliferation. Based on these findings, the potential for targeting BAF57 as a prostate cancer…

…therapeutic option was examined. First, expression of BAF57 was verified in human prostate tissue specimens, with possible enhanced expression observed in metastatic samples. Subsequent molecular analyses determined that the primary region of interaction…

…occurred between the DBD/hinge region of AR and the proline-rich/HMG domain of BAF57. The N-terminal binding region of BAF57 was then shown to reduce AR recruitment to AR target genes, inhibit AR target gene activity, and decrease prostate cancer cell…

…proliferation. Together, the data herein establish the SWI/SNF chromatin remodeling complex, specifically BAF57, as a valid target for the treatment of prostate cancer. Acknowledgments: The success of my graduate career could not have been possible without…

…26 28 Chapter III: BAF57 Governs Androgen Receptor Activity and AndrogenDependent Proliferation through SWI/SNF A. Abstract………………………………………………………………… B. Introduction……………………………………………………………. C. Materials and Methods………………………………………………. D. Results…

…E. Discussion……………………………………………………………... F. References…………………………………………………………….. 31 32 36 45 53 59 Chapter IV: Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: a novel platform to control AR activity A. Abstract………………………………………………………………… B…

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