Luiz O.F. Penalva PhD Awarded CPRIT Grant to Study New Glioblastoma (GBM) Regulator
Glioblastoma (GBM) is the most common and most aggressive brain tumor type among adults with a 14 months average patient survival. Despite all genomic efforts in recent years, novel therapies based on GBM common mutations and alterations have been disappointing. To build an alternative route, we have been focusing on oncogenic RNA binding proteins (RBPs). RBPs modulate gene expression via RNA processing, mRNA decay, and translation and are often deregulated in tumors. Considering their broad regulatory nature, RBP targeting is a robust option that could be used to block multiple oncogenic pathways simultaneously.
We have identified SERBP1 (Serpine RNA binding protein 1) as a novel oncogenic RBP in GBM. SERBP1 high expression correlates with poor prognosis and response to treatment in GBM. Functional and genomic analyses established that SERBP1 regulates critical metabolic routes (One Carbon, Methyl, and MTA cycles) and this regulation lead to activation of the cell cycle, the proliferation of glioma stem cells (GSCs), tumor growth and silencing of genes implicated in neuronal differentiation. SERBP1 is the first example of an RBP functioning as a central regulator of metabolism. Importantly, we determined that SERBP1 controls methionine production and ultimately affects histone methylation (H3K27me3). Therefore, SERBP1 functions as a bridging factor between metabolism and epigenetic regulation.
We propose SERBP1 targeting as an alternative to treat GBM. Disruption of SERBP1 regulatory functions will not only affect metabolic routes contributing to the growth of cancer cells but also revert epigenetic silencing, promoting neuronal differentiation.
To increase the translational aspect of our project and deal with GBM complexity, we will conduct our experiments in GSCs from three different GBM subgroups. Our first goal is to expand our initial analysis and define SERBP1’s specific impact on epigenetic regulation (H3K27me3 profile in particular). To do so, we will conduct RNA-seq and ChIP-seq analyses in SERBP1 control and knockdown cells. Ultimately, we will combine the results of both analyses to build a SERBP1 centered network. In the second part of our study, we will perform a structural/biochemical study to define the SERBP1 RNA binding domain and use this knowledge to devise a strategy to identify a SERBP1 inhibitor via high throughput screening (HTS). We will test then its potential to block SERBP1 binding to RNA in vitro and in GBM cells and to function as an anti-tumorigenic agent.
Specific Aim 1 – Define SERBP1 impact on epigenetic regulation. Task 1) Determine using genomic methods the alterations in gene expression and histone methylation profile driven by SERBP1 knockdown in glioma stem cells (GSCs). Task 2) Corroborate our hypothesis that the SERBP1 impact on the Methyl Cycle causes specific changes in the H3K27me3 profile, ultimately affecting the expression of genes implicated in neuronal differentiation.
Specific Aim 2. Define a combined strategy to target GBM. Task 1) Map SERBP1 domain(s) required for RNA binding and use this information to screen for inhibitors. Task 2) Evaluate SERBP1 inhibitor by itself and in combination with epigenetic inhibitors as a potential approach to target GBM cells.
- Understand the function of a novel oncogenic factor. SERBP1 emerges as an important oncogenic factor in GBM and other malignancies. Our study will provide a comprehensive view of the SERBP1 regulatory role in GBM, establish its target genes, and link to cancer-relevant pathways. The results of our study could also help understand SERBP1 role in brain development and function.
- Characterize an important link between cancer metabolism and epigenetic regulation. Cancer cells become dependent on alternative metabolic routes to improve nutrient acquisition to meet the tumor energy and growth demands. Targeting “cancer metabolism” is a viable option in cancer therapy and has increased its relevance in recent years. Similarly, gene silencing via histone methylation (H3K27me3) is an important contributor of GBM poorly differentiated state, and inhibition of its regulators (PRC2 members) has been recently explored in cancer therapy. Characterization of SERBP1 provides an opportunity to explore a novel link between these two relevant processes.
- Targeting RNA binding proteins (RBPs) in cancer therapy. There is a growing number of RNA binding proteins implicated in tumorigenesis with several examples of oncogenic RBPs. A few RBP inhibitors are currently being tested in clinical trials. The strategy to be developed in this application to target SERBP1 and explore its use in combination therapy will help establish approaches to identify inhibitors against other oncogenic RBPs. This is particularly important in the case of GBM due to the lack of therapeutic options. RBP targeting offers a choice to handle GBM complexity and heterogeneity by interfering with several oncogenic pathways at once.