Vol. 7, Issue 12, Part A (2025)

The ubiquitin-proteasome pathway (UPP) is a highly regulated protein degradation system essential for maintaining cellular homeostasis. Its dysregulation plays a central role in cancer development by altering the stability of key proteins involved in cell-cycle control, apoptosis, DNA repair, and hypoxia signaling. Ubiquitination, mediated by E1, E2, and E3 enzymes, determines whether proteins undergo proteasomal degradation or participate in non-proteolytic signaling. Aberrant activity of E3 ligases and deubiquitinating enzymes leads to uncontrolled degradation or accumulation of oncogenes and tumor-suppressor proteins such as p53, cyclins, p27, and Bcl-2. The pathway also regulates apoptosis through modulation of Bcl-2 family proteins, caspases, and IAPs, enabling cancer cells to evade programmed cell death. Additionally, hypoxia-inducible factors (HIFs) are tightly controlled by VHL-mediated ubiquitination, and their dysregulation promotes angiogenesis and tumor progression. Understanding UPP biology has enabled development of novel anticancer therapies, including proteasome inhibitors and E3-targeted drugs.