SUMOylation in glioblastoma – A review
Targeting SUMOylation in glioblastoma opens new avenue for therapeutic interventions and biomarker discovery
image: The diagram illustrates the SUMOylation pathway, including its key steps: maturation, activation, conjugation, ligation, and de-modification. The process begins with SUMO precursors undergoing maturation by SUMO-specific proteases (SENPs). Activated SUMO proteins are transferred to the E1 enzyme (SAE1-SAE2 heterodimer) in an ATP-dependent process. Subsequently, the activated SUMO is handed over to the E2 enzyme (Ubc9) through conjugation. E3 ligases then facilitate the transfer of SUMO from Ubc9 to the lysine residue of target proteins, forming an isopeptide bond. Finally, SENPs catalyze deSUMOylation to reverse the modification, ensuring dynamic regulation of protein function
Credit: Wiktoria Dubanosow, Bartosz Lenda, Marta Żebrowska-Nawrocka, Dagmara Szmajda-Krygier, Rafał Świechowski, Ewa Balcerczak
Glioblastoma, a grade IV malignancy, is the most common type of glioma. Despite therapeutic interventions, such as surgical resection, chemotherapy, and radiotherapy, patients have a poor median overall survival. Alterations in the cell cycle progression, induced by genomic instability and post-translational modifications, are associated with the oncogenic transformation of gliomas. Understanding these mechanisms in glioma progression may help identify new targets and aid in the development of novel anti-glioma therapeutics.
A recent review published in the Genes & Diseases journal, by researchers from Medical University of Lodz, explores the role of SUMOylation, a post-translational modification, in the malignant transformation of glioblastoma, providing new insights into the identification of biomarkers and therapeutic targets.
The authors begin by outlining the SUMOylation process and its components. The E1-activating enzyme facilitates the activation of the SUMO protein, and Ubc9 (also known as UBE2I) catalyzes the transfer of the activated SUMO protein onto the target protein. Conversely, the SUMO proteases (SENPs) aid in deSUMOylation. The authors then list the SUMO target proteins, while describing how their SUMOylation influences the progression of various tumors.
Dysregulation of the SUMOylation mechanism is associated with cancer initiation and patient prognosis. Increasing evidence shows the critical role of SUMOylation in the development of gliomas. Enhanced SUMOylation increases the survival of GBM cells by protecting them from DNA damage, contributing to chemo- and radio-therapy resistance. SUMOylation affects cellular metabolism by enhancing the glycolytic and the pentose-phosphate pathways, thereby modifying the bioenergetics of the system. By stabilizing the Hif-1 alpha protein, it promotes the epithelial-to-mesenchymal transition of glioma cells.
The authors then describe the interplay between SUMOylation and phosphorylation processes during cell cycle regulation. SUMOylation stabilizes AKT activity, influencing proliferation, migration, and angiogenesis, while high AKT expression correlates with lower survival rates in GBM patients.
Furthermore, Ubc9 shows potential as a promising biomarker; its overexpression is associated with glioma progression, while its inhibition reduces proliferation and increases apoptosis of GBM cells. This suggests that Ubc9 and its associated molecular pathways may serve as potential therapeutic targets in glioma.
Numerous drugs and natural compounds, such as topotecan, chlorogenic acid, and melatonin, regulate SUMOylation to exert inhibitory effects on glioma progression. The authors suggest that future research in glioma should be directed towards developing specific inhibitors, identifying predictive biomarkers, integrating SUMOylation-based therapies, and understanding its cross-talk with other PTMs and its role in glioma stem cells.
In conclusion, this review offers insights into the role of SUMOylation in GBM progression, suggesting that “targeting SUMOylation represents a promising but unexplored strategy in GBM treatment