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Review
. 2021 Aug 31;13(17):4402.
doi: 10.3390/cancers13174402.

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Antti Kukkula  1 , Veera K Ojala  1   2   3   4 , Lourdes M Mendez  5 , Lea Sistonen  4   6 , Klaus Elenius  1   3   4   7 , Maria Sundvall  1   7
Affiliations
Review

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Antti Kukkula et al. Cancers (Basel). .

Abstract

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

Keywords: cancer; post-translational modification (PTM); protein inhibitor of activated STAT (PIAS); sentrin-specific protease (SENP); small ubiquitin-like modifier (SUMO).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The enzymatic SUMO cascade. (A) SENPs cleave off amino acids from precursor SUMO to produce a mature SUMO. (B) SAE1/SAE2 forms of a thioester bond between SUMO’s GG and catalytic cysteine residue of SAE1/2. (C) Thioester bond is formed between SUMO’s GG and catalytic cysteine residue of Ubc9. (D) Ubc9 catalyzes formation of an isopeptide bond between GG and target substrate’s lysine residue often with assistance of an E3 ligase. (E) SENPs deconjugate SUMO from the substrate.
Figure 2
Figure 2
Examples of SUMO-modification regulation of key oncogenic substrates. (A) SUMOylation of PML-RARα in K160 and recruitment of co-repressors is required for APL cell differentiation blockade, self-renewal and immortalization. (B) PIAS3 promotes transactivation of estrogen receptor α (ERα) and proliferation of breast cancer cells via SUMO-dependent and independent mechanisms, whereas PIAS1 has a predominantly repressive effect on ERα. (C) SENP1-mediated deSUMOylation of androgen receptor (AR) promotes AR-dependent transactivation and proliferation of prostate cancer cells that is counteracted by PIAS1- and PIAS2-induced SUMO1-modification of AR.
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