COLLABORATIVE ACTION OF MOLECULAR CHAPERONES, UBIQUITIN E3 LIGASES AND SIGNALING MOLECULES IN THE REVERSAL OF GLIOBLASTOMA AND OTHER BRAIN TUMORS

Abstract

Brain tumors represents a class of tumors that arises from the malignant transformation of the astrocytes and glial cells. Despite various advancements, treatment options remain limited to chemotherapy and radiotherapy followed by surgery giving an overall survival of 14~15 months. These therapies are somewhere restricted in giving a better survival and cure. There is a need for new therapeutics that could potentially target various brain tumors based on molecular pathways and pathology. Here ubiquitin E3 ligases and heat shock proteins can be used as targets as they bind a wide array of substrates and therefore, can be attractive targets for new inhibitors. Through our study, we have tried to sort various ubiquitin E3 ligases based on their expression, pathways to which these ligases are associated, and mutational frequencies, and then we tried to screen potent inhibitors against the most favorable E3 ligase and heat shock proteins as very few studies are available concerning inhibition of E3 ligase and heat shock proteins in GBM and ependymomas. We performed an integrated omics analysis to predict the mutual regulatory differential HSP signatures that were associated with both glioblastoma and ependymomas. Further, we explored the various common dysregulated biological processes operating in both the tumors, and were analyzed using functional enrichment, gene ontology along with the pathway analysis of the predicted HSPs. We established an interactome network of protein-protein interaction (PPIN) to identify the hub HSPs that were commonly associated with GBMs and ependymoma. To understand the mutual molecular mechanism of the HSPs in both malignancies, transcription factors, and miRNAs overlapping with both diseases were explored. Moreover, a transcription factor-miRNAs-HSPs coregulatory network was constructed along with the prediction of potential candidate drugs that were based on perturbation-induced gene expression analysis. Finally, the ranking of the drugs was arranged based on various drug scores. In conclusion, this study gave a spotlight on the mutual targetable HSPs, biological pathways, and regulatory ix | P a g e signatures associated with GBMs and ependymoma with an improved understanding of crosstalk involved. Additionally, the role of therapeutics was also explored against HSP90AB1. These findings could potentially be able to explain the interplay of HSP90AB1 and other HSPs within these two malignancies.