Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM can be divided into two prognostic groups based on a clinically validated gene expression profile (GEP), with class 1 GEP being associated with good prognosis and class 2 GEP with bad prognosis. Each tumor class is associated with specific driver mutations, several of which were discovered in our laboratory. In particular, the highly metastatic Class 2 tumors are associated with inactivating mutations in the tumor suppressor BAP1. However, a major gap exists in our knowledge of how BAP1 mutations lead to metastatic death, which has thwarted the development of targeted precision therapy. To address this deficiency, my objective is to identify and characterize proteins that interact with BAP1. In preliminary studies, I performed a biotin-labeling mass spectrometry technique called BioID2 and identified HDAC1 as a novel BAP1-interacting protein. Thus, I propose to investigate the role of HDAC1 in mediating the tumor suppressor function of BAP1. I hypothesize that BAP1 regulates the epigenetic functions of HDAC1 by maintaining it in a de-ubiquitinated state. Accordingly, I predict that mutational inactivation of BAP1 deregulates HDAC1, leading to changes in histone acetylation and gene expression that promote tumor progression. I will test this hypothesis with the following Aims: (1) Determine how BAP1 interacts with HDAC1 and regulates its ubiquitination state, and (2) Identify how BAP1 loss deregulates transcription through histone acetylation changes catalyzed by HDAC1. My overall objective is to characterize the BAP1-HDAC1 interaction and the consequences of its disruption by BAP1 mutations as an avenue to discovering new therapeutic strategies.

Public Health Relevance

Uveal melanoma (UM) is the most common primary eye cancer in adults with over half of patients developing metastatic disease to the liver. We have identified a new interaction between BAP1 and HDAC1 that may be driving tumor progression when BAP1 is lost. Ultimately, this proposed research will help us understand this interaction providing us new insights into the progression of this deadly cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA243426-01
Application #
9835695
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcneil Ford, Nicole
Project Start
2019-09-30
Project End
2023-09-29
Budget Start
2019-09-30
Budget End
2020-09-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146