Cancer Letters

Cancer Letters

Volume 469, 28 January 2020, Pages 301-309
Cancer Letters

Mini-review
SUMOylation homeostasis in tumorigenesis

https://doi.org/10.1016/j.canlet.2019.11.004Get rights and content

Highlights

  • We summarized the research progress and impacts of SUMOylation homeostasis in tumorigenesis.

  • We provided an overview of the mechanism of aberrant SUMOylation involved in cancer regulation and progression..

  • We expounded the clinical need and potential therapeutic targets of aberrant SUMOylated proteins in cancers.

Abstract

Small ubiquitin-like modifier (SUMO), a critical regulatory modification protein, is involved in various biological processes, such as gene expression, genome maintenance and DNA damage repair (DDR). Numerous recent studies have revealed that disturbed SUMOylation and deSUMOylation homeostasis contribute to tumorigenesis. Abnormal alterations of key factors in the SUMO modification are closely related to cancer development and progression, indicating that the restoration of SUMOylation homeostasis may serve as a promising therapeutic strategy. In this review, we summarize the process and function of SUMOylation, clarify the ‘dual-edged sword’ functions of SUMOylation in diversified cancers and put forth future research prospects.

Introduction

Small ubiquitin-like modifier (SUMO) is used to modify a variety of proteins by its covalent attachment to these proteins as a posttranslational modification (PTM). This highly dynamic and reversible modification is an important stress response mechanism in cells and appears to be dysregulated in many cancers. There are 5 mammalian SUMO isoforms: SUMO1, SUMO2/3, SUMO4 and SUMO5. Although the SUMO isoform nomenclature is inconsistent, the human SUMO2 and SUMO3 proteins share 97% sequence identity and cannot be distinguished by antibodies; however, SUMO1 is quite different from SUMO2/3, as 53% of the sequence of SUMO1 differs from that of SUMO2/3 [33]. SUMO1 and SUMO2/3 conjugate distinct substrates in vivo and show different abilities to form SUMO chains. The difference in chain forming ability is attributed to the Lys residues near the amino termini of SUMO2/3, which serve as SUMO acceptor sites, while in SUMO1, these residues are not readily apparent. SUMO1 and SUMO2/3 paralogues are characterized by proteolytic maturation, which refers to exposing a carboxy-terminal diglycine (GG) motif by the sentrin specific peptidase (SENP). SUMO4, another SUMO family member, is similar to SUMO2/3 except that the SUMO4 sequence contains a proline (Pro 90) instead of a glutamine that leads to inert maturation by SENP. SUMO5, a newly discovered SUMO variant, was recently found in several primate tissues [56]. Despite the differences among these isoforms, the enzymes that activate and conjugate each type of SUMO protein are the same.

Section snippets

The process of SUMOylation and deSUMOylation

The attachment of SUMO is catalyzed through an enzymatic cascade involving an E1 activating enzyme, an E2 conjugating enzyme and an E3 ligase [16] (Fig. 1). The SUMO E1 enzyme, a heterodimer composed of SUMO-activating enzyme subunit 1 (SAE1) and SAE2, forms the C-terminus of SUMO [11]. Once the SUMO adenylate is formed, it is transferred to UBC9, the single E2 conjugating enzyme, forming an E2-SUMO thioester bond via an isopeptide linkage to a target lysine residue. Although very few proteins

The physiological function of SUMOylation

Recent data suggest that up to 3000 human proteins are modified by SUMO under certain circumstances [39]. SUMO is mainly found in the nucleus and is essential for the regulation of various nuclear processes such as gene expression, genome maintenance and DNA damage repair and, therefore, cell cycle control and nucleocytoplasmic transport. In addition to its impact on gene networks, SUMOylation plays direct roles in transcriptional regulation and affects protein stability, activity and

Aberrant SUMO modification contributes to various tumors

Given the essential role of SUMOylation in regulating various biological processes, it is not surprising that SUMOylation plays a crucial role in tumorigenesis. To date, numerous aberrantly SUMOylated proteins have been identified in multiple cancers (Fig. 3 and Table 2). However, these findings on the mechanistic link between SUMOylation and tumorigenesis represent merely the tip of the iceberg.

Conclusion and future perspectives

In recent years, we have seen a renaissance of interest in the field of posttranslational modification. An extensive array of ubiquitylation and phosphorylation events have been uncovered. However, there remains a limited understanding of SUMOylation events. Fortunately, with the rapid development of bioinformatics and mass spectrometry, a variety of methods can be used to explore SUMO-modified substrates and sites accurately and efficiently. These advancements have aided in deciphering the

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No.81672709 to J.H.) and the Science and Technology Commission of Shanghai (17DZ2260100 to X.F.).

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