Distinctive tumorigenic significance and innovative oncology targets of SUMOylation

Abstract

Protein SUMOylation, a post-translational modification, intricately regulates diverse biological processes including gene expression, cell cycle progression, signaling pathway transduction, DNA damage response, and RNA metabolism. This modification contributes to the acquisition of tumorigenicity and the maintenance of cancer hallmarks. In malignancies, protein SUMOylation is triggered by various cellular stresses, promoting tumor initiation and progression. This augmentation is orchestrated through its specific regulatory mechanisms and characteristic biological functions. This review focuses on elucidating the fundamental regulatory mechanisms and pathological functions of the SUMO pathway in tumor pathogenesis and malignant evolution, with particular emphasis on the tumorigenic potential of SUMOylation. Furthermore, we underscore the potential therapeutic benefits of targeting the SUMO pathway, paving the way for innovative anti-tumor strategies by perturbing this dynamic and reversible modifying process.

Keywords: Cancer; Cancer hallmarks; Cancer therapy; Post-translational modification; SUMOylation.

Figure 1

The SUMOylation cascade. SUMOylation is a multi-step enzymatic cascade catalyzing SUMOs covalently conjugating to substrate proteins. This dynamic and reversible SUMOylation process consists of multi-step actions, involving maturation, activation, conjugation, ligation, and deconjugation. SENPs cleave the amino acids in the C-terminal of inactive precursors of SUMO proteins to expose their diglycine (-GG) motif. SAE1/2 combines its cysteine site with the C-terminal of SUMO under the premise that ATP hydrolysis provides energy. Under the synergy of UBC9 and SUMO E3 ligase, the SUMOs are covalently conjugated to a lysine (K) in the SUMOylation consensus motif ψKx[E/D]. SENPs also orchestrate the deSUMOylation by removing SUMOs from substrate proteins.

Figure 2

Biological significance manipulated by SUMOylation in tumors. Protein SUMOylation governs a spectrum of biological effects in tumors, involving protein stability, protein-protein interaction, protein translocation, phase separation, transcriptional activation, and genomic instability, by which it participates in the disruption of cell homeostasis via inducing aberrance of gene expression, cell cycle progression, signaling pathway transduction, DNA damage response, RNA metabolism, etc.

Figure 3

Role of SUMO molecules in tumors. SUMOylation cascade is frequently identified in tumor initiation, progression, and response to therapies. In most instances, SUMOylation plays an indispensable role in exacerbating cancer progression. However, some SUMOylation molecules have been proven to act as tumor-suppressive roles in certain human tumors, even playing distinct roles in the same tumor.

Figure 4

The biological functions of SUMOylation cascade in tumors. SUMOylation participates in the acquisition or maintenance of cancer hallmarks, such as tumor invasion, metastasis, cancer stem cell self-renewal, epigenetic reprogramming, immune evasion, metabolic reprogramming, and programmed cell death escape. SUMOylation is involved in tumor invasion and metastasis via administrating tumor angiogenesis, EMT, etc. SUMOylation induces cancer stem cell maintenance and self-renewal via governing cancer stemness-related genes and pathways. SUMOylation manages epigenetic reprogramming via perturbing transcriptional activation, protein interaction, protein localization, protein stability, and RNA metabolism. SUMOylation facilitates tumor immune evasion via altering the tumor microenvironment and abolishing immune surveillance. SUMOylation promotes metabolic reprogramming via stimulating the Warburg effect. SUMOylation enhances the escape of programmed cell death via blocking apoptosis and autophagy. EMT: epithelial-to-mesenchymal transition.

Figure 5

Cellular stressors that induce SUMOylation in cancers. SUMOylation which plays a critical role in maintaining cellular homeostasis is evoked by diverse cellular stresses, including viruses, hypoxia, gut microbiota, and lactic acid. Viruses such as HBV, EBV, and HPV have been confirmed to contribute to cancers via manipulating the SUMOylation process. Hypoxia has been identified as the inducement the SUMOylation in tumors. Gut microbiota and its metabolites such as pks+ E. coli and SCFAs participate in the tumorigenesis via modulating the SUMOylation in p53 and NF-κB signaling. Lactate may promote tumor progression via stabilizing the anaphase-promoting complex (APC/C) in a SUMOylation-dependent manner. SCFA: short-chain fatty acid.