Targeting SUMO Signaling to Wrestle Cancer

Kroonen, Jessie S; Vertegaal, Alfred C.O.

doi:10.1016/j.trecan.2020.11.009

Cited by 65 publications

(41 citation statements)

References 142 publications

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“…The SUMO pathway is increasingly viewed as a potential therapeutic target in cancer [262], and several inhibitors of SUMO E1-activating, E2-conjugating and deconjugating enzymes have been identified (Table 2).…”

Section: Therapeutic Targeting Of the Sumo Pathwaymentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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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.

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Section: Therapeutic Targeting Of the Sumo Pathwaymentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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“…SUMOylation is a post-translational modification that can reversibly connect SUMO (small ubiquitin-like modifier) to lysine residues in the substrates ( Celen and Sahin, 2020 ; Kroonen and Vertegaal, 2020 ). The process of SUMOylation is catalyzed by the cascade reaction of E1 activating enzyme (SAE1 and UBA2), E2 conjugating enzyme (UBE2I), and E3 ligase (PIAS1, PIAS2, PIAS3, PIAS4, and RANBP2).…”

Section: Introductionmentioning

confidence: 99%

Expression and Prognosis Analysis of SUMOylation Regulators in Oral Squamous Cell Carcinoma Based on High-Throughput Sequencing

Meng

2021

Front. Genet.

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IntroductionOral squamous cell carcinoma (OSCC) originates from oral mucosal epithelial cells, accounting for more than 90% of oral cancers. The relationship between the expression and prognostic role of SUMOylation regulators in OSCC is rarely studied.Materials and methodsThe expression and survival data of OSCC were derived from TCGA and GEO databases. Wilcoxon test was used to determine the differential expression of the SUMOylation regulators. A prognostic model based on SUMOylation regulator-related genes was constructed by Cox regression. Gene set enrichment analysis was applied to predict the potential biological functions that the genes might be involved in.ResultsRANBP2 and SENP6 had the highest SNV frequency. Eleven genes including PIAS3, RANBP2, USPL1, SENP6, SENP2, SENP5, SAE1, UBA2, PIAS4, UBE2I, and SENP3 were highly expressed in OSCC. The prognostic model based on nine SUMOylation-regulated genes (TRIM37, UFM1, FUBP1, CCNT1, FXR1, HMG20A, RANBP3, SPATA5, and DDX23) had a strong ability to predict the prognosis of OSCC.ConclusionThis study might provide targets for prognostic evaluation and targeted therapy of patients with OSCC.

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“…SUMO is crucial for various types of cancer due to its reversible nature in cell cycle progression and genome integrity [ 34 ]. Apart from RANBP2, multiple SUMO enzymes are responsible for cancer progression and represent targetable cancer metabolic biomarkers [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

RANBP2 Activates O-GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes

Liu

Chen

Xiao

et al. 2021

Cancers

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O-GlcNAcylation is an important post-translational modification (PTM) jointly controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Aberrant hyper-O-GlcNAcylation is reported to yield hepatocellular carcinoma (HCC) malignancy, but the underlying mechanisms of the OGT/OGA imbalance responsible for HCC tumorigenesis remain largely unknown. Here, we report that RAN-binding protein 2 (RANBP2), one of the small ubiquitin-like modifier (SUMO) E3 ligases, contributed to malignant phenotypes in HCC. RANBP2 was found to facilitate CCAAT/enhancer-binding protein alpha (CEBPα) SUMOylation and degradation by direct interplay with CEBPα. As a transcriptional factor, CEBPα was verified to augment OGA transcription, and further experiments demonstrated that RANBP2 enhanced the O-GlcNAc level by downregulating OGA transcription while not affecting OGT expression. Importantly, we provided in vitro and in vivo evidence of HCC malignant phenotypes that RANBP2 triggered through an imbalance of OGT/OGA and subsequent higher O-GlcNAcylation events for oncogenic proteins such as peroxisome proliferative-activated receptor gamma coactivator 1 alpha (PGC1α) in a CEBPα-dependent manner. Altogether, our results show a novel molecular mechanism whereby RANBP2 regulates its function through CEBPα-dependent OGA downregulation to induce a global change in the hyper-O-GlcNAcylation of genes, such as PGC1α, encouraging the further study of promising implications for HCC therapy.

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Targeting SUMO Signaling to Wrestle Cancer

Cited by 65 publications

References 142 publications

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Expression and Prognosis Analysis of SUMOylation Regulators in Oral Squamous Cell Carcinoma Based on High-Throughput Sequencing

RANBP2 Activates O-GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes

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