The Role of Melanocyte Differentiation in Uveal Melanoma Progression

Date of Award

Spring 5-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Uveal melanoma is a rare, but extremely deadly disease. Gaining a better understanding of disease progression has huge implications for the treatment of metastatic disease. The relatively non-aggressive class 1 tumors, which rarely metastasize, closely resemble a normal, differentiated melanocyte, whereas the aggressive class 2 tumors, which almost always metastasize, are much less differentiated and more stem-like in nature. This clear distinction led us to further investigate the role that differentiation is playing in uveal melanoma disease progression.

The retinoblastoma protein (Rb) is functionally inactivated in almost all uveal melanomas and upon investigation of Rb's potential role in the differentiation of melanocytes, we found that Rb physically interacts with the master regulator of melanocyte differentiation, MITF, and that it is able to cooperate with MITF to induce expression of melanocyte differentiation genes. Our evidence suggests that this role of Rb is dependent on it being in its active, hypophosphorylated form, which implies that the inactivated form of Rb that is found in uveal melanoma maybe unable to cooperate with MITF to induce differentiation.

In addition to this potential role for Rb in uveal melanoma progression, we also identified a metastasis suppressor gene, BAP1 that is mutated in the overwhelming majority of the aggressive class 2 tumors. We found that loss of BAP1 within the melanocytic lineage does not affect traditional measures of tumorigenicity, but rather it induces a dedifferentiated, stem-like state. In addition we found that BAP1 loss led to significantly increased levels of ubiquitinated H2A. This function of BAP1 is in direct opposition to the PRC1 complex and when BAP1-deficient cells were treated with an HDAC-inhibitor, one of the targets of which is PRC1, the levels of ubiquitinated H2A were returned to normal levels. Interestingly treatment of BAP1-deficient cells with an HDAC-inhibitor restored the expression of melanocyte differentiation genes to normal levels, and shifted tumor cells towards a more differentiated phenotype. These data suggest that loss of BAP1 is contributing to a loss of melanocytic cell identity that may contribute to melanoma disease progression and points to the use of HDAC-inhibitors as a potential treatment for metastatic disease.

Language

English (en)

Chair and Committee

J. William Harbour

Committee Members

Jason D Weber, Kristen L Kroll, Joshua B Rubin, David C Beebe, Katherine N Weilbaecher

Comments

Permanent URL: https://doi.org/10.7936/K78050JS

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