Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the “Warburg effect,” play an essential part in tumor metabolic reprogramming. In addition, fatty acids are harnessed to satisfy the increased requirement for the phospholipid components of biological membranes and energy. Moreover, the anabolism/catabolism of amino acids, such as glutamine, cystine, and serine, provides nitrogen donors for biosynthesis processes, development of the tumor inflammatory environment, and signal transduction. The ubiquitin–proteasome system (UPS) has been widely reported to be involved in various cellular biological activities. A potential role of UPS in the metabolic regulation of tumor cells has also been reported, but the specific regulatory mechanism has not been elucidated. Here, we review the role of ubiquitination and deubiquitination modification on major metabolic enzymes and important signaling pathways in tumor metabolism to inspire new strategies for the clinical treatment of cancer.

The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC.

Studies have suggested a close association between hyperactivation of the catenin beta 1 gene (CTNNB1) and the occurrence and progression of colorectal cancer (CRC). Here, we report that Pyridoxal kinase (PDXK) promotes the development of colorectal cancer through Wnt signaling pathway. The expression of PDXK is elevated in CRC patients and is associated with an unfavourable prognosis. Genetic depletion of PDXK significantly inhibited CRC cell viability, viability, and migration both in vitro and in vivo. Furthermore, we observed that overexpression of PDXK enhanced CRC cell viability, invasion, and migration, and these effects were dependent on its kinase activity. GSEA revealed a strong association between PDXK expression and the Wnt signaling pathway, which was validated through luciferase reporter assays and RT-qPCR. Mechanistically, PDXK was found to activate the Wnt signaling pathway by interacting with GSK-3β and releasing beta-catenin from the GSK-3β destruction complex, thereby promoting tumorigenesis. These findings provide direct insights into the molecular mechanisms underlying the functions of PDXK in CRC and suggest it as a potential therapeutic target for combating colorectal cancer.