Characterization of EZH2s Pro-Oncogenic Activity as a Transcriptional Modulator in NF1-Associated MPNST
Abstract
Background: Approximately 100,000 Americans with neurofibromatosis type I (NF1) suffer a constellation of clinical signs and symptoms, including the abnormal growth of nerve tissues leading to malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly aggressive and have a high risk of recurring and spreading. The major challenge when treating these resistant tumors is the lack of effective strategies. Currently available drugs do not work, and surgical removal is very often impossible due to the tumor location or because the tumor has already spread to other parts of the body. Due to these limitations, some studies have shown that the 5-year survival rate is less than 25%. In an effort to understand the molecular processes responsible for these aggressive tumors, we propose to focus on EZH2 and its potential role in development of MPNST. EZH2 is the catalytic subunit of the Polycomb Repressor Complex 2 (PRC2) that is responsible for inactivation, or silencing, of genes that promote tumor growth. A fully functional PRC2 also requires additional protein subunits SUZ12 and EED, which recent studies have shown to be deficient in MPNST as a result of gene loss and/or inactivation. Interestingly enough, however, no such genetic mutation has been identified in human MPNST tissue for EZH2. We believe this suggests an important function of EZH2 that is favored and protected in MPNST. In fact, we observe high levels of EZH2 in aggressive tumors. Also, when EZH2 is blocked or inhibited, MPNSTs stop growing, suggesting that EZH2 has an important role in MPNST. Our proposal is that EZH2 assumes the role of a gene activator in the absence of SUZ12 and/or EED by interacting with PRC2-independent proteins to facilitate processes that promote tumor growth. Applicability and Impact: These studies propose to define the role of EZH2 in the absence or presence of SUZ12 and EED. We think that in the absence of its partners, EZH2 may behave abnormally as a gene activator. By understanding how EZH2 behaves and which molecules interact with EZH2, we will be able to (1) identify potential drug targets for the treatment of N1-MPNST, (2) define the context in which EZH2 inhibition could be an effective therapeutic strategy for NF1-associated MPNST, and (3) design more effective combination treatments with EZH2 inhibition when applicable to avoid resistance to drug treatment. The overall objective of this proposal is to characterize how EZH2 s dual role in gene silencing and activation is affected by the presence or absence of genetic aberrations in the other PRC2 complex members, SUZ12 and EED. The rationale for the proposed research is that understanding the interplay of EZH2 s role in gene silencing and activation will allow the identification of potential drug targets for the treatment of N1-MPNST.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710219
Entities
People
- Keila E Torres
Organizations
- United States Army
- University of Texas at Austin