Targeting the Ubiquitin-Dependent Transcriptional and Epigenetic Landscape in Cancer

Abstract

Ubiquitin and ubiquitin-like (Ub/UbL) pathways play essential roles in regulating protein function and homeostasis. Dysregulation of these pathways is intimately associated with tumorigenesis. Furthermore, sensitivity to proteotoxic stress is emerging as an “Achilles heel” of cancer cells and tumors. Purpose of Review The purpose of this review was to discuss the recent discoveries in ubiquitin-regulated transcriptional and epigenetic mechanisms and potential inhibitors, targeting these mechanisms for cancer therapeutics. Recent Findings The remarkable discovery that proteasome inhibitors, such as bortezomib, are powerful therapeutics in multiple myeloma has led to the development of inhibitors that target activation enzymes (E1s) of distinct Ub/UbL pathways. Moreover, ubiquitin-dependent transcriptional and epigenetic networks have surfaced as essential for gene regulation. Components of these networks include E2s, E3s, deubiquitinating enzymes, and ancillary factors that enhance stability and activity of oncogenes, or inactivate tumor suppressors. Other regulators impinge upon the chromatin landscape of cancer, which was previously considered “undruggable.” Interestingly, approaches for targeting “degradation-resistant tumors,” where key oncogenic regulators evade their physiological degradation, are on the horizon. Additionally, inhibitors of Ub-related enzymes capable of stalling the activity of oncogenic epigenetic complexes, which all contain intrinsic ubiquitin-related activity, are emerging as potent inhibitors for their oncogenic transcription. Summary Fundamental mechanisms regarding the role of Ub/UbL pathways in cancer are now translated into inhibitors targeting Ub/UbL-dependent oncogenic gene expression. These small-molecule inhibitors and experimental drugs are making their way to the clinic, providing hope for cancer patients.