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SWI/SNF Chromatin Remodeling Enzymes: Epigenetic Modulators in Melanoma Invasiveness and Survival

Saladi, SrinivasVinod
http://rave.ohiolink.edu/etdc/view?acc_num=mco1310065995

Abstract Details

2011, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
SWI/SNF enzymes are multi subunit complexes consisting of an ATPase subunit, either BRG1 or BRM. They act as epigenetic modulators and remodel the chromatin in an ATP dependent manner. The SWI/SNF complex has 9-12 BRG1 or BRM associated factors called (BAFs). Earlier studies from our lab showed that BRG1 interacts with Microphthalmia associated transcription factor (MITF) to promote melanocyte differentiation. MITF is a lineage addiction oncogene in melanoma that regulates melanoma proliferation and metastasis. Several of the SWI/SNF subunits have been demonstrated to behave as tumor suppressors in mice and been found to be down regulated in many forms of cancer. However, our lab has shown that although, BRG1 or BRM is down-regulated in a small subset of melanoma cell lines, one catalytic subunit is always retained and the other SWI/SNF subunits are expressed at high levels compared to normal melanocytes. This has led to the hypothesis, that in melanoma, SWI/SNF enzymes interact with MITF and other transcription factors to modulate melanoma metastasis and survival. In the first study we demonstrate that BRG1 is significantly upregulated in stage IV metastatic melanomas compared to stage III melanoma and normal skin. We found that BRG1 modulates the expression of genes that code for components of the extracellular matrix and regulators of adhesion. We found that BRG1 promotes adhesion of melanoma cells to laminin and collagen but inhibits adhesion to fibronectin. Furthermore, in vitro BRG1 promotes the invasive potential of the cells by upregulating matrix metalloproteinase 2 (MMP2) expression at the transcriptional level. Thus, our studies demonstrate that BRG1 epigenetically modulates melanoma invasive ability in vitro, suggesting that BRG1 plays a role in melanoma metastasis. SWI/SNF enzymes have been demonstrated to regulate the response to DNA damage by promoting DNA repair and cell cycle checkpoint controls. Earlier studies from the lab showed that BRG1 promotes melanoma resistance to the DNA damaging agent, cisplatin. In the present study we determined that BRG1 also promotes survival in response to DNA damage induced by UVB radiation. We found that in addition to promoting DNA repair and regulating cell cycle proteins, BRG1 directly modulates the apoptotic pathway by activating expression of the melanoma-inhibitor of apoptosis gene (ML-IAP). ML-IAP is a potent inhibitor of the apoptotic pathway, and a potential target for melanoma treatment. In melanoma cells, ML-IAP expression is regulated by a cooperative activation loop involving BRG1 and MITF that promotes permissive chromatin structure and an active epigenetic signature on the ML-IAP promoter. Our studies suggest that an effective option for treating melanoma may be the use of epigenetic drugs that target either BRG1 or chromatin remodeling enzymes that function in concert with BRG1.
Ivana de la Serna, Ph. D. (Committee Co-Chair)
Khew-Voon Chin, Ph. D. (Committee Co-Chair)
William Maltese, Ph. D. (Committee Member)
Manohar Ratnam, Ph. D. (Committee Member)
James Trempe, Ph. D. (Committee Member)
Kam Yeung, Ph. D. (Committee Member)
162 p.
Biomedical Research; Cellular Biology; Molecular Biology
SWI/SNF; Chromatin remodeling; DNA repair; Invasion; Apoptosis

Recommended Citations

Citations

  • Saladi, S. (2011). SWI/SNF Chromatin Remodeling Enzymes: Epigenetic Modulators in Melanoma Invasiveness and Survival [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1310065995

    APA Style (7th edition)

  • Saladi, SrinivasVinod. SWI/SNF Chromatin Remodeling Enzymes: Epigenetic Modulators in Melanoma Invasiveness and Survival. 2011. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1310065995.

    MLA Style (8th edition)

  • Saladi, SrinivasVinod. "SWI/SNF Chromatin Remodeling Enzymes: Epigenetic Modulators in Melanoma Invasiveness and Survival." Doctoral dissertation, University of Toledo, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1310065995

    Chicago Manual of Style (17th edition)

mco1310065995
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© 2011, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.