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The Role of Bromodomain Containing Protein Nine (BRD9) in Melanogenesis and Melanoma

BASUROY, TUPA
http://rave.ohiolink.edu/etdc/view?acc_num=mco1535031325513441

Abstract Details

2018, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Cancer Biology).
One major challenge associated with the treatment of skin cancers is the development of resistance to chemotherapeutic agents. The most dangerous form of skin cancer is malignant melanoma, which develops from the transformation of melanocytes. Melanocytes are cells in the epidermis that produce the pigment melanin and protect our skin against damage. Heterogeneous chromatin remodeling complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) interacts with the master regulators of melanocyte differentiation and melanoma oncogenes to regulate the expression of genes important for melanogenesis and melanoma proliferation. SWI/SNF contains either Brahma-related gene-1 (BRG1) or Brahma (BRM) as the ATPase and an assortment of associated factors (BAFs). BRG1 and BRM as well as some BAFs have bromodomains which bind to acetylated lysine residues in histone tails. Little is known about the role of the bromodomain proteins in regulating SWI/SNF function. Small molecules that specifically inhibit the association of these bromodomain containing proteins with chromatin can be used as tools to interrogate bromodomain function and may have therapeutic potential.I-BRD9 is a chemical inhibitor specific for Bromodomain Containing Protein Nine (BRD9), a newly identified bromodomain containing component of SWI/SNF complexes that have BRG1 as the catalytic subunit. This dissertation highlights studies aimed at defining the role of BRD9 in melanogenesis and melanoma, using I-BRD9. First, I provide evidence that BRD9 has functions in melanogenesis. Administration of I-BRD9 to melanocyte precursors inhibits melanin synthesis and expression of genes that regulate melanocyte function. Decreased expression of genes that regulate melanin synthesis is associated with altered chromatin structure at the regulatory sites. Our studies demonstrate several therapeutically relevant genes in melanoma are impaired by I-BRD9 in melanocytes. Next, I establish that BRD9 has functions in melanoma. The critical role of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation with increased proliferation of melanoma cells is underscored by several studies. The pharmacological inhibition of BRAF is associated with the dismal prognosis of melanoma coupled to its tendency to recur and develop resistance to BRAF inhibition. This has generated wide interest in identifying new therapeutic targets to address melanoma that are refractory to conventional therapy. My findings highlight that BRD9 is highly expressed in a subset of melanoma cell lines and it immunoprecipitates with BRG1 in melanoma cells. Administration of I-BRD9 in melanoma cells is associated with decreased expression of genes that regulate melanoma proliferation, invasion and survival. Moreover, we notice the effects of BRD9 inhibition and BRAF inhibition in BRAF mutant melanoma cells in harnessing the transcription factors and their downstream effectors, which are otherwise upregulated to confer melanoma resistance subsequent to BRAF inhibition alone. Also, depletion of BRD9 by siRNA confirms the effects of I-BRD9. Collectively, these findings will be crucial in identifying the critical protein targets regulating melanogenesis and driving melanoma progression, thereby providing the foundation for future studies on melanoma cells that are refractory to therapy.
Ivana L de la Serna (Committee Chair)
Kandace Williams (Committee Member)
Randall Ruch (Committee Member)
Robert Trumbly (Committee Member)
Kam Yeung (Committee Member)
Dayanidhi Raman (Committee Member)
129 p.
Biomedical Research; Medicine; Oncology
Melanogenesis SWI SNF Bromodomains BRD9 I-BRD9 Melanoma BRAFV600E FOXD3 ERBB3

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Citations

  • BASUROY, T. (2018). The Role of Bromodomain Containing Protein Nine (BRD9) in Melanogenesis and Melanoma [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1535031325513441

    APA Style (7th edition)

  • BASUROY, TUPA. The Role of Bromodomain Containing Protein Nine (BRD9) in Melanogenesis and Melanoma. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1535031325513441.

    MLA Style (8th edition)

  • BASUROY, TUPA. "The Role of Bromodomain Containing Protein Nine (BRD9) in Melanogenesis and Melanoma." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco1535031325513441

    Chicago Manual of Style (17th edition)

mco1535031325513441
© 2018, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.