PRC2-Dependent Enhancer Reprogramming Promotes MPNST Pathogenesis
Abstract
People with neurofibromatosis 1 (NF1) are at risk of developing malignant peripheral nerve sheath tumors (MPNSTs) over the course of their lifetime. Currently, available drugs do not work and surgical removal is often impossible due to the tumor location or because the tumor has spread to other parts of the body. Due to these limitations, some studies have shown that the 5-year survival rate can be less than 25%. Therefore, the long-term goal of our research group is to leverage a deep understanding of the epigenetic modifications in MPNST toward the identification of effective therapies. By epigenetic modifications, we refer to the external alterations that occur to DNA that turn genes “on” or “off.” Epigenetic modifications alter the physical structure of DNA. They do not change the DNA sequence, but instead, they affect how cells “read” genes. One example of an epigenetic change is histone modification. Histones are proteins that DNA wraps around. Some histone modifications relax the DNA and make it accessible to proteins that “read” genes. Conversely, other histone modifications make the DNA or chromatin very compact and do not allow the cell to “read” those DNA areas. Recent work found that 70-90% of MPNSTs carry mutations in genes SUZ12 and EED. These genes, along with EZH2 (catalytic unit), are part of a protein complex called polycomb repressive complex 2 (PRC2) that modifies histone 3 and silences genes that are necessary for tumor growth. Building on this finding, this project will systematically look at (1) how the chromatin (DNA and histones) structure is modified after SUZ12 loss (PRC2 loss), (2) how the chromatin structure contributes to uncontrolled cellular growth, and (3) what role EZH2, the catalytic component of PRC2, assumes in the absence of its partners, SUZ12 and EED. Objective and Rationale: The objective of proposed research is to define the epigenetic deregulation associated with MPNST development and elucidate how the changes in chromatin promote tumor progression. The rationale for the proposed study is that understanding the chromatin alterations due to PRC2 loss (SUZ12/EED loss) and understanding the role of EZH2 in the context of SUZ12/EED loss can bridge the gap in our understanding of the molecular mechanisms driving MPNST progression. Our preliminary work suggests that the chromatin undergoes specific changes and that EZH2 has a role in gene activation at specific DNA locations in the context of MPNSTs with PRC2 loss. This new concept challenges the current paradigm of MPNST that has only focused on PRC2-mediated repression as the molecular mechanism for tumor progression. Applicability and Impact: The proposed study will delineate the aberrations that occur in chromatin structure (epigenetic changes) during transformation of neurofibroma to MPNST. The translational applicability of the proposed research is that (1) associating the chromatin alterations due to PRC2 loss and understanding the role of EZH2 in the context of SUZ12 or EED loss can bridge the gap in our understanding of the molecular mechanisms driving MPNST progression and (2) this will help identify the contexts in which pharmacologic inhibition of a chromatin state will be an effective treatment strategy for MPNSTs. Our studies will have a positive impact by providing preclinical data that can inform future clinical trials. Consequently, the knowledge gained from this work could expedite appropriate treatment and therefore potentially advance patient care and improve patient survival. Potential Clinical Applications and Benefits: The proposal addresses the clinical need for effective treatments for MPNST. We propose preclinical studies that will help identify the contexts in which pharmacologic inhibition of a chromatin state in combination with inhibition of critical tumorigenic drivers will be an effective treatment strategy for MPNST. Pursuit of the combination therapies that work in concert
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010098
Entities
People
- Keila E Torres
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army