- The ubiquitin–proteasome system (UPS) plays a fundamental role in maintaining cellular homeostasis by regulating the degradation of proteins that control growth, division, DNA repair, and apoptosis. In cancer, this system becomes profoundly dysregulated, allowing malignant cells to bypass normal regulatory constraints and acquire hallmark features such as uncontrolled proliferation, resistance to cell death, genomic instability, and metastatic potential. Because UPS activity influences nearly every signalling pathway relevant to tumour biology, it is now recognised as one of the most important molecular systems driving cancer development and progression.
- The UPS functions through two coordinated steps: selective tagging of proteins with ubiquitin and their subsequent degradation by the 26S proteasome. In healthy cells, this ensures that short‑lived, damaged, or regulatory proteins are removed at the correct time. In cancer, however, mutations, altered expression, or hijacking of UPS components lead to inappropriate stabilisation of oncogenic proteins or excessive degradation of tumour suppressors. One of the most striking examples is the regulation of p53, the master tumour suppressor. Under normal conditions, p53 is kept at low levels through ubiquitination by Mdm2. Many cancers overexpress Mdm2 or acquire mutations that enhance its activity, resulting in excessive p53 degradation and loss of genome‑protective functions. Similarly, mutations in the E3 ligase FBW7 stabilise oncogenic proteins such as Cyclin E, Myc, and Notch, driving uncontrolled proliferation.
- UPS dysregulation also affects the cell cycle directly. Cyclins, CDKs, and CDK inhibitors are all UPS substrates, meaning that altered ubiquitination can accelerate or deregulate cell‑cycle transitions. Overactive SCF complexes may degrade p27 or p21 too rapidly, removing critical brakes on proliferation. Conversely, abnormal stabilisation of cyclins promotes continuous cell‑cycle progression. These changes allow cancer cells to divide even under conditions that would normally trigger arrest or apoptosis.
- Beyond proliferation, the UPS plays a central role in DNA damage responses. Proteins such as BRCA1, ATM, ATR, Chk1, and Chk2 depend on ubiquitination for activation, localisation, or turnover. When UPS components malfunction, DNA repair pathways become compromised, enabling cancer cells to tolerate high levels of genomic instability. This instability fuels tumour evolution, allowing malignant clones to acquire mutations that promote survival, drug resistance, and metastasis.
- Apoptosis is another process tightly controlled by UPS activity. Anti‑apoptotic proteins such as Bcl‑2 and Mcl‑1 are often stabilised in cancer due to reduced ubiquitination, while pro‑apoptotic proteins may be degraded prematurely. This imbalance allows cancer cells to evade programmed cell death even when exposed to stress, DNA damage, or chemotherapy. UPS‑mediated regulation of NF‑κB, HIF‑1α, and β‑catenin further supports survival signalling, angiogenesis, and adaptation to hypoxia within the tumour microenvironment.
- UPS components also influence metastasis by regulating epithelial–mesenchymal transition (EMT), cytoskeletal dynamics, and cell adhesion. Ubiquitination of E‑cadherin, integrins, and polarity proteins affects cell motility and invasion, enabling cancer cells to detach, migrate, and colonise distant tissues. Altered degradation of HIF‑1α promotes angiogenesis and supports tumour growth under low‑oxygen conditions.
- Because UPS dysregulation is so pervasive in cancer, it has become an attractive therapeutic target. Proteasome inhibitors such as bortezomib and carfilzomib are now widely used in multiple myeloma and lymphoma, exploiting the dependence of malignant cells on heightened proteasomal activity. Newer strategies, including E3 ligase modulators and PROTACs, aim to selectively degrade oncogenic proteins by redirecting UPS machinery. These approaches represent a major shift in cancer therapy, allowing precise manipulation of protein stability rather than simply blocking enzymatic activity.
- In summary, the ubiquitin–proteasome system is deeply embedded in the molecular architecture of cancer. By controlling the stability of proteins that govern proliferation, DNA repair, apoptosis, signalling, and metastasis, the UPS determines whether a cell behaves normally or acquires malignant traits. Its dysregulation is both a driver of tumour biology and a powerful therapeutic vulnerability, making it one of the most important systems to understand in modern cancer research.
