While the impact of protein ubiquitination has been extensively studied in regulating functional protein- protein interaction, protein subcellular localization and protein stability, the interplay between the ubiquitination and epigenetic machinery in orchestrating EGFR signaling in gliomagenesis has not been drawn our attention until recently. This project targets the new aspects of the ubiquitin-pathway in regulating histone H2A that in turn modulates EGFR signaling pathway in gliomagenesis. Monoubiquitination of histone H2A is one of the most abundant histone posttranslational modifications in mammalian cells. H2A ubiquitination represents an important mechanism for many regulatory transcriptional programs. Accumulating evidence supports a role of H2A ubiquitination in glioblastoma. However, how H2A ubiquitination is regulated in glioblastoma is unknown. Studies outlined in this proposal will exam the functions and mechanisms of an EGFR induced lncRNA, Lnc-EPAT, in H2A ubiquitination and tumorigenesis of glioblastoma. We will use a variety of molecular and cell-based assays, and animal models, to determine 1) whether the aberrant EGFR activation causes Lnc-EPAT overexpression in glioblastoma and the mechanisms underlying EGFR signaling-induced Lnc-EPAT expression; 2) the role and mechanisms for Lnc-EPAT in sustaining H2A ubiquitination and epigenetic regulation of EGFR pathway; 3) the functional significance and mechanisms of EGFR- Lnc-EPAT-H2Aub in glioblastoma tumorigenesis. Finally, we will determine the clinical significance of our findings using human tumor specimens. We predict that completion of these studies will contribute to a better understanding of the molecular mechanisms for H2A ubiquitination and glioblastoma tumorigenesis. Furthermore, accomplishing our goals is highly relevant to the development of novel therapeutic agents that inhibit Lnc-EPAT for better combating glioblastoma. Thus, our studies may revolutionize our understanding and treating glioblastoma.
Glioblastomas are the most common and fatal brain tumors which are highly proliferative in nature. In this application, we propose to define a new mechanism of glioblastomas cell growth and tumorigenesis controlled by a long noncoding RNA through regulating H2A ubiquitination and epigenetics modulation of EGFR signaling pathway. Our work will significantly contribute to our understanding of mechanisms of glioblastomas and help develop effective approaches to treat this devastating disease.
