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

Gu, Yunru; Fang, Yuan; Wu, Xi; Xu, Tingting; Hu, Tong; Xu, Yangyue; Ma, Pei; Wang, Qiang; Shu, Yongqian

doi:10.1186/s40164-023-00420-3

Cited by 11 publications

(5 citation statements)

References 209 publications

(224 reference statements)

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“…In this study, we revealed heightened small ubiquitin-like modifier protein 2 ( Sumo2 )-mediated SUMOylation activity in residual tumors after iRFA of HCC. SUMOylation is a post-translational modification process involving the attachment of SUMO proteins to substrates, is linked with increased tumorigenic potential and poorer clinical outcomes [ 13 ]. It has been reported to interfere with the IFN-1 signaling by modifying multiple targets.…”

Section: Introductionmentioning

confidence: 99%

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Liu,

Li,

Chen

et al. 2024

J Nanobiotechnol

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Background Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. Results This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors. Conclusions These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC. Graphic Abstract

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Section: Introductionmentioning

confidence: 99%

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Liu,

Li,

Chen

et al. 2024

J Nanobiotechnol

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“…Cancer proliferation, progression, and response to therapies depend upon the interaction between malignant cells and tumor microenvironment. Proteins involved in tumorigenesis rely on SUMOylation ( 49 ). PIAS1 and PIASxα co-localize with the resident protein of PML nuclear bodies that are renowned as SUMO1 and SUMO2.…”

Section: The Process Of Sumoylationmentioning

confidence: 99%

PIAS family in cancer: from basic mechanisms to clinical applications

Li,

Rasul,

Sharif

et al. 2024

Front. Oncol.

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Protein inhibitors of activated STATs (PIAS) are proteins for cytokine signaling that activate activator-mediated gene transcription. These proteins, as versatile cellular regulators, have been described as regulators of approximately 60 proteins. Dysregulation of PIAS is associated with inappropriate gene expression that promotes oncogenic signaling in multiple cancers. Multiple lines of evidence have revealed that PIAS family members show modulated expressions in cancer cells. Most frequently reported PIAS family members in cancer development are PIAS1 and PIAS3. SUMOylation as post-translational modifier regulates several cellular machineries. PIAS proteins as SUMO E3 ligase factor promotes SUMOylation of transcription factors tangled cancer cells for survival, proliferation, and differentiation. Attenuated PIAS-mediated SUMOylation mechanism is involved in tumorigenesis. This review article provides the PIAS/SUMO role in the modulation of transcriptional factor control, provides brief update on their antagonistic function in different cancer types with particular focus on PIAS proteins as a bonafide therapeutic target to inhibit STAT pathway in cancers, and summarizes natural activators that may have the ability to cure cancer.

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“…The dynamic and reversible nature of SUMOylation involves a series of enzymatic steps, including maturation, activation, conjugation, ligation, and deconjugation 2 (Figure 1 ). Mechanistically, sentrin-specific proteases (SENPs) catalyze the proteolytic cleavage of the C-terminal amino acids of inactive SUMO precursor proteins, exposing their diglycine (-GG) motif and promoting maturation.…”

Section: Sumoylation Cascade and Biological Significance In Tumorsmentioning

confidence: 99%

“…SUMOylation, identified in the 1990s, is a dynamic and reversible protein post-translational modification 1 . In a nutshell, this process is a multi-step enzymatic cascade catalyzing the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine (K) residues of substrate proteins 2 . Typically, SUMOylation and ubiquitination compete for substrate proteins; however, unlike ubiquitination, which often targets proteins for degradation, SUMOylation primarily maintains protein stability.…”

Section: Introductionmentioning

confidence: 99%

Distinctive tumorigenic significance and innovative oncology targets of SUMOylation

Zhou,

Deng,

et al. 2024

Theranostics

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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.

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

Cited by 11 publications

References 209 publications

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

PIAS family in cancer: from basic mechanisms to clinical applications

Distinctive tumorigenic significance and innovative oncology targets of SUMOylation

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