Balancing Ubiquitination and Deubiquitination in Apoptotic Protein Stability and Cancer Cell Survival

Programmed cell death is essential for maintaining cellular homeostasis, and its evasion is a defining hallmark of cancer. The threshold for apoptosis is largely determined by the stability of pro- and anti-apoptotic proteins, which is tightly regulated by the ubiquitin-proteasome system (UPS). In this system, E1, E2, and E3 enzymes sequentially attach ubiquitin chains that mark substrates for degradation by the 26S proteasome, whereas deubiquitinating enzymes (DUBs) reverse these modifications to stabilize specific substrates. The opposing actions of E3 ubiquitin ligases and DUBs therefore form a dynamic network that fine-tunes the abundance of key apoptotic regulators and ultimately determines cell survival or death. In this review, we summarize how DUBs control the stability of central components of both the intrinsic and extrinsic apoptotic pathways, including the p53 pathway, BCL-2 family proteins such as MCL-1, and anti-apoptotic regulators including cellular FLICE-like inhibitory protein (c-FLIP) and inhibitor of apoptosis proteins (IAPs). We also discuss how linkage-specific ubiquitin editing at death receptor complexes influences the balance between survival and apoptosis. Finally, we discuss how dysregulation of DUB-mediated protein stability promotes apoptotic evasion in cancer and highlight the therapeutic potential of DUB-targeted strategies, including catalytic inhibitors and stabilization approaches such as deubiquitinase-targeting chimeras (DUBTACs).