Ubiquitination plays a key role in cancer stem cell function and treatment resistance

This review highlights the critical role of ubiquitination in governing the functionality of cancer stem cells (CSCs), shedding light on potential therapeutic targets for combating tumor progression, recurrence, and drug resistance. Published in Genes & Diseases, this article explores the intricate mechanisms through which the ubiquitin (Ub) system regulates key pathways essential for CSC maintenance and survival.

Ubiquitination, a fundamental post-translational modification, plays a pivotal role in protein stability, cellular signaling, and gene expression, particularly in the context of CSCs. Dysregulation of the Ub system has been identified as a driving force behind tumorigenesis and metastasis, making it a crucial area of study for developing novel anti-cancer therapies. The review delves into the E3 ubiquitin ligases, a specialized class of enzymes responsible for targeting specific proteins for degradation, and their interaction with CSCs. These ligases, alongside deubiquitinases, modulate transcription factors such as SOX2, OCT4, KLF4, and c-Myc, all of which play a crucial role in CSC self-renewal and differentiation.

The study further examines the interplay between ubiquitination and key signaling pathways, including Notch, Wnt/β-catenin, Hedgehog, and Hippo-YAP, which regulate stem-like properties in cancer cells. By influencing these pathways, ubiquitination emerges as a potentially powerful therapeutic target to disrupt the aggressive nature of CSCs. The involvement of the Ub-proteasome system (UPS) in maintaining CSC characteristics highlights an opportunity for drug development focused on modulating ubiquitin ligases and deubiquitinases to selectively degrade or stabilize proteins essential for CSC survival.

This review underscores the need for targeted therapies aimed at exploiting the vulnerabilities of the Ub system in CSCs. Existing proteasome inhibitors, such as bortezomib and carfilzomib, have shown promise in certain cancers, but further research into specific E3 ligases and DUBs could pave the way for more precise and effective cancer treatments. The potential of combining Ub-targeted therapies with traditional chemotherapy, immunotherapy, and targeted drugs represents a novel frontier in oncological treatment strategies.

As cancer research advances, understanding the molecular mechanisms behind CSC regulation through ubiquitination offers new hope for improved therapeutic interventions. By identifying key regulatory factors and pathways, this review provides a comprehensive framework for the development of next-generation anti-cancer therapies, marking an important step toward overcoming cancer recurrence and treatment resistance.