Title : Targeting oncogenic YY1 in resistant glioblastoma multiforme
Abstract:
Background: The oncogenic transcription factor Yin Yang 1 (YY1) is critical in the pathogenesis of glioblastoma multiforme (GBM), a highly aggressive brain tumor Given the poor response of GBM to current treatments, there is an urgent need for a new therapeutic intervention. We first examined the various immunosuppressive roles mediated by YY1 overexpression in GBM, particularly its effects on the tumor microenvironment (TME) and mechanisms underlying immune evasion.
Methods: This study analyzed the various signaling pathways mediated by YY1 that regulate GBM growth and resistance to therapies including immunotherapy. In addition, we utilized RNA-sequencing expression data (level 3) from the TCGA-GBM dataset comprising 153 GBM tumors and five normal tissues to examine YY1 expression in GBM, differences in immune cell infiltration between GBM and normal tissue, and between YY1-high (n = 77) and YY1-low (n = 76) expressing GBMs. Furthermore, immune scores in these tissues were assessed using CIBERSORTx.
Results: The reported findings of YY1 overexpression in GBM revealed several oncogenic properties and some examples are : (i)YY1 regulation of SNHG5 and activation of the p38/MAPK pathway (ii) YY1 activation the PCAT6 and IGF2BP1 oncogenes (iii) YY1 transcriptional regulation of LINC00466 associated with reduced survival (iv) YY1 pivotal role in GSCs and (v) YY1 regulation of MMP1 and invasion. Our bioinformatic analyses supported the significant role of YY1 inhibitory role in the immune response against GBM. YY1 regulates immune cell compartments by increasing immunosuppressive cells and reducing anti-tumor immune cells. The analyses also show overexpression of checkpoint inhibitor receptors (PD-1, TIM-3, LAG-3, TIGIT, CTLA-4) on T cells and inhibitory ligands (PD-L1, PD-L2, SIGLEC-15) on tumor and TME cells.
Conclusion: Based on the pleiotropic anti-tumor activities of YY1 in GBM, targeting YY1 can be achieved with different therapeutic approaches, such as using nanoparticles, YY1 inhibitors, targeted gene therapy, and exosome-based delivery systems. Although these methods are complex, effectively targeting YY1 holds promise for transforming GBM treatment strategies, creating new possibilities for innovative therapies and improved patient outcomes. Further investigations into the molecular mechanisms of YY1 are crucial for developing personalized medicine strategies to address the diverse nature of GBM and improve patient outcomes.
Audience Take Away Notes:
- Elucidates how YY1 overexpression contributes to the development and progression of GBM, including its impact on the tumor microenvironment (TME) and mechanisms of immune evasion
- Insights into the specific signaling pathways regulated by YY1 that promote GBM growth and resistance to therapies, such as the p38/MAPK pathway, and the activation of oncogenes like PCAT6 and IGF2BP1
- Details how YY1 influences immune cell compartments by increasing immunosuppressive cells and reducing anti-tumor immune cells, along with the overexpression of immune checkpoint inhibitors on T cells and inhibitory ligands on tumor cells
- Various potential therapeutic approaches for targeting YY1 in GBM will be discussed, including the use of nanoparticles, YY1 inhibitors, targeted gene therapy, and exosome-based delivery systems, highlighting the promise of these strategies for improving patient outcomes
- Covers the bioinformatic analysis of YY1 expression in GBM using RNA-sequencing data, and the clinical implications of these findings for developing personalized medicine strategies to treat GBM
