UBC Theses and Dissertations
Role of SWI/SNF chromatin remodeling complex in melanoma development Lin, Hanyang
Human cutaneous malignant melanoma is an aggressive form of skin cancer, for its ability to metastasize rapidly and its resistance to conventional radiotherapy and chemotherapy. The mammalian SWI/SNF complex mediates ATP-dependent chromatin remodeling processes that are critical for transcriptional regulation, control of cellular processes, and involvement in DNA repair. Therefore, aberrant expression of SWI/SNF chromatin remodeling complex is involved in cancer development. To investigate the role of SWI/SNF complex in the development of melanoma, we used tissue microarray technology and immunohistochemistry to evaluate the expression of SNF5, the common core subunit, and BRG1, the ATPase subunit, in melanocytic lesions at different stages, and we analyzed the correlation between SNF5 and BRG1 expression and clinicopathologic variables and patient survival. In addition, we also investigated the role of SNF5 in nucleotide excision repair (NER), a type of DNA repair mechanism that removes ultraviolet-induced DNA lesions. We found that reduced SNF5 expression is significantly associated with melanoma progression and a worse patient survival, and that SNF5 is an independent prognostic factor for human melanoma. Furthermore, we showed that downregulation of SNF5 protein level in melanoma cell lines enhanced chemoresistance of melanoma cells. This suggests that SNF5 plays an important role in melanomagenesis and may serve as a promising prognostic marker for melanoma. BRG1 expression, on the other hand, was found to be increased in primary and metastatic melanoma compared to dysplastic nevi. Knockdown of BRG1 in human melanoma cell lines reduced cell proliferation due to G1 phase arrest. This suggests that BRG1 might play a role in the initiation stage of melanomagenesis. As for the role of SWI/SNF complex in NER, our current observation demonstrated that in human keratinocytes, SNF5 is required for efficient removal of CPD and is required for UV-induced histone acetylation. In human melanoma cells, SNF5 does not seem to play a major role in NER, for it is not required for removal of CPD and UV-induced global chromatin relaxation. Taken together, these data implicate that SWI/SNF complex plays an essential role in melanoma development and may serve as a promising therapeutic target for melanoma.
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