Author ORCID Identifier
0000-0001-6561-7878
Date of Graduation
8-2021
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Kunal Rai, Ph.D.
Committee Member
Menashe Bar-Eli, Ph.D.
Committee Member
Glen Traver Hart, Ph.D.
Committee Member
Min Gyu Lee, Ph.D.
Committee Member
Haoqiang Ying, M.D., Ph.D.
Abstract
Metastatic melanoma is one of the most aggressive cancers. In recent years, the survival rate has improved with the introduction of immunotherapy. Our lab conducted an in vivo ORF screen to identify potential drivers of metastasis. UCHL5/UCH37 was identified as one of the top candidates. UCHL5 is a deubiquitinating enzyme and interacts with the 26S proteasome complex and the INO80 chromatin remodeling complex. While UCHL5 has been shown to be overexpressed in many cancers, it has not been well characterized in melanoma. We investigated the role of UCHL5 in metastatic melanoma in vitro through overexpressing and knocking down UCHL5 in primary and metastatic melanoma cell lines, Western Blotting, RNA-sequencing, ATAC-sequencing, ChIP-sequencing, and in vivo by using a mouse model. Mice that were inoculated with B16F10 shUCHL5 cells and subsequently treated with an isotype control led to reduced tumor burden. However, mice that were inoculated with B16F10 shUCHL5 cells and were also treated with anti-mouse PD1 led to increased tumor burden. We find that UCHL5 plays a role in the progression of metastatic melanoma and contributes to an increased tumor burden. These findings can provide insight into how we approach treatment for metastatic melanoma, including how we target and modulate the function of UCHL5.
Keywords
UCHL5, UCH37, melanoma, metastasis, epigenome, immunotherapy