The emerging roles of SUMOylation in the tumor microenvironment and therapeutic implications

Abstract

Tumor initiation, progression, and response to therapies depend to a great extent on interactions between malignant cells and the tumor microenvironment (TME), which denotes the cancerous/non-cancerous cells, cytokines, chemokines, and various other factors around tumors. Cancer cells as well as stroma cells can not only obtain adaption to the TME but also sculpt their microenvironment through a series of signaling pathways. The post-translational modification (PTM) of eukaryotic cells by small ubiquitin-related modifier (SUMO) proteins is now recognized as a key flexible pathway. Proteins involved in tumorigenesis guiding several biological processes including chromatin organization, DNA repair, transcription, protein trafficking, and signal conduction rely on SUMOylation. The purpose of this review is to explore the role that SUMOylation plays in the TME formation and reprogramming, emphasize the importance of targeting SUMOylation to intervene in the TME and discuss the potential of SUMOylation inhibitors (SUMOi) in ameliorating tumor prognosis.

Keywords: Clinical implications; Hypoxia; Immune response; Inflammation; Metabolism; Post-translational modification; SUMOylation; Tumor microenvironment.

Fig. 1

The SUMO procedure diagram and its function in various tumors. SUMO proteins are firstly processed by SENP, and after the formation of a high-energy thioester bond between the C-terminal SUMO and active site cysteine of SAE1/2, activated SUMO is then transferred to a cysteine residue in the active site of Ubc9. It is finally transferred to a target lysine with the help of Ubc9 and SUMO E3 ligase. The expression and functions in different tumors of SUMO E1, E2, E3 ligases and SENPs are also depicted in this figure

Fig. 2

Crosstalk between SUMOylation related enzymes and hypoxia signaling pathway. SUMOylation related enzymes regulate HIF-1a stability and transcriptional activity through directly mediating its SUMOylation and indirectly influencing other participants involved in hypoxia signaling pathway, causing expression level alteration of critical genes that modulating cancer cells biological processes such as metastasis, angiogenesis, and glycolysis. Meanwhile, hypoxia can also affect expression of some actors via monitoring their SUMOylation state

Fig. 3

The role of SUMOylation in cancer metabolism pathways. This diagram focuses on SUMO modified metabolic enzymes, closely associated signaling pathways and TFs. Noteworthy, glucose metabolism is the most important metabolic pathway regulated by SUMOylation, contributing to metabolic reprogramming such as “Warburg effect”

Fig. 4

Functional sites of SUMOylation inhibitors. Ginkgolic acid, anacardic acid, and kerriamycin B blocks SAE1/2, while Davidiin and tannic acid impairs formation of the SAE1/2-SUMO intermediate. ML-792, TAK981, COH-000, and ML-93 inhibits SUMO E1 as well. Spectomycin B and GSK145, 2-D08, and SUBINS bind to UBC9, disturbing its interaction with SUMO. Triptolide, Momordin Ic and streptonigrin respectively inhibit SENP1 and disrupt SENP1-SUMO1 interaction. GN6958 and Ebselen suppress SENP1 and SENP2 respectively. There is no E3 inhibitor under research. Green inhibitors are natural compound while blue ones are synthetic product

Fig. 5

A summary of SUMOylation in the TME and therapeutic implications