Explore the vast range of titles available.

ObjectivePancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.DesignWe analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.ResultsWe observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.ConclusionSUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

The COVID-19 is an infectious disease caused by SARS-CoV-2 infection. A large number of clinical studies found high-level expression of pro-inflammatory cytokines in patients infected with SARS-CoV-2, which fuels the rapid development of the disease. However, the specific molecular mechanism is still unclear. In this study, we found that SARS-CoV-2 Nsp5 can induce the expression of cytokines IL-1β, IL-6, TNF-α, and IL-2 in Calu-3 and THP1 cells. Further research found that Nsp5 enhances cytokine expression through activating the NF-κB signaling pathway. Subsequently, we investigated the upstream effectors of the NF-κB signal pathway on Nsp5 overexpression and discovered that Nsp5 increases the protein level of MAVS. Moreover, Nsp5 can promote the SUMOylation of MAVS to increase its stability and lead to increasing levels of MAVS protein, finally triggering activation of NF-κB signaling. The knockdown of MAVS and the inhibitor of SUMOylation treatment can attenuate Nsp5-mediated NF-κB activation and cytokine induction. We identified a novel role of SARS-CoV-2 Nsp5 to enhance cytokine production by activating the NF-κB signaling pathway.

SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma. SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.

SUMO (Small Ubiquitin-like Modifier) conjugation onto target proteins has emerged as a very influential class of protein modification systems. SUMO1/2 double mutant plants are nonviable, underlining the importance of SUMO conjugation to plant survival. Once covalently bound, SUMO can alter a conjugated protein's stability and/or function. SUMO conjugation is a highly dynamic process that can be rapidly reversed by the action of SUMO proteases. The balance between the conjugated/deconjugated forms is a major determinant in the modulation of SUMO-target function. Despite the important mechanistic role of SUMO proteases in model plants, until now the identity or the function of these regulatory enzymes has not been defined in any crop plant. In this report, we reveal the ubiquitin-like protease class of SUMO protease gene family in rice (Oryza sativa) and demonstrate a critical role for OsOTS1 SUMO protease in salt stress. OsOTS-RNAi rice plants accumulate high levels of SUMO-conjugated proteins during salt stress and are highly salt sensitive; however, in non-salt conditions, they are developmentally indistinguishable from wild-type plants. Transgenic rice plants overexpressing OsOTS1 have increased salt tolerance and a concomitant reduction in the levels of SUMOylated proteins. We demonstrate that OsOTS1 confers salt tolerance in rice by increasing root biomass. High salinity triggers OsOTS1 degradation, indicating that increased SUMO conjugation in rice plants during salt stress is in part achieved by down-regulation of OTS1/2 activity. OsOTS1 is nuclear localized indicating a direct requirement of OsOTS1-dependent deSUMOylation activity in rice nuclei for salt tolerance.

Main conclusionSUMOylation of SLR1 at K2 protects productivity under salt stress, possibly by modulation of SLR1 interactome.DELLA proteins modulate GA signaling and are major regulators of plant plasticity to endure stress. DELLAs are mostly regulated at the post-translational level, and their activity relies on the interaction with upstream regulators and transcription factors (TFs). SUMOylation is a post-translational modification (PTM) capable of changing protein interaction and has been found to influence DELLA activity in Arabidopsis. We determined that SUMOylation of the single rice DELLA, SLENDER RICE1 (SLR1), occurs in a lysine residue different from the one identified in Arabidopsis REPRESSOR OF GA (RGA). Artificially increasing the SUMOylated SLR1 levels attenuated the penalty of salt stress on rice yield. Gene expression analysis revealed that the overexpression of SUMOylated SLR1 can regulate GA biosynthesis, which could partially explain the sustained productivity upon salt stress imposition. Furthermore, SLR1 SUMOylation blocked the interaction with the growth regulator YAB4, which may fine-tune GA20ox2 expression. We also identified novel SLR1 interactors: bZIP23, bHLH089, bHLH094, and OSH1. All those interactions were impaired in the presence of SUMOylated SLR1. Mechanistically, we propose that SUMOylation of SLR1 disrupts its interaction with several transcription factors implicated in GA-dependent growth and ABA-dependent salinity tolerance to modulate downstream gene expression. We found that SLR1 SUMOylation represents a novel mechanism modulating DELLA activity, which attenuates the impact of stress on plant performance.

Purpose High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research. Methods SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF). Results We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8 + T (T ex ) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8 + T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models. Conclusions This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC. Graphical abstract

Background KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRAS G12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS -mutant cancers. Many treatments for KRAS -mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS -mutant cancer cells. Methods The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS -mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. Results We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS -mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin–proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS -mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. Conclusions We found that MYC downregulation occurred via SUMOylation inhibition in KRAS -mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS -mutant cancers by enhancing DNA damage accumulation.

Background Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer. Methods We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy. Results Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy. Conclusion The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of DUX4 , normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and DUX4 expression has been suggested, the precise mechanisms that regulate DUX4 transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of Dux , the DUX4 homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of DUX4 in human muscle cells. We demonstrate that TAK‑981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces DUX4 expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving DUX4 expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and DUX4 transcription, providing a potential therapeutic strategy to modulate DUX4 expression in FSHD.

SUMOylation, a dynamic regulatory process in post-translational modifications (PTMs) mediated by small ubiquitin-like modifier (SUMO) ligases and deSUMOylases, regulates protein function through reversible lysine conjugation. Emerging evidence has identified tumor-mediated hijacking of SUMOylation in both malignant cells and immune components as a novel immune evasion mechanism. This review represents a comprehensive update on how tumor-intrinsic SUMOylation modulates tumor immunity-related JAK/STAT, MHC-I, NF-κB, IFN-I/II pathways and other key proteins to drive its immune evasion, and immune cell-intrinsic SUMOylation in regulating natural killer (NK) and T cell cytotoxicity, dendritic cell (DC) maturation, and macrophage polarization. Tumor immunotherapy is a new potential strategy for cancer, mainly represented by immune checkpoint inhibitions (ICIs), which exhibits poor efficacy in head and neck squamous cell carcinoma (HNSCC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. Targeting SUMOylation of tumors presents high potential to synergistically improve the therapeutic effect of ICIs. Preclinical studies have shed light on the therapeutic potential of the combination of SUMOylation inhibitors such as TAK-981 or 2-D08 with ICIs, thus significantly improving tumor prognosis. As current phase I trials suggest dose-dependent toxicity of TAK-981, there is a need for targeted delivery systems; AI-assisted screening of novel SUMOylation inhibitors (SUMOi) which are FDA approved serves as another potential approach; besides, antibodies against these pivotal SUMOylated molecules in tumors could be conjugated with SUMOi to restore the activity of specific proteins in tumor microenvironment. In all, our review proposes that current or other novel strategies for SUMOylation inhibition stands as a promising adjuvant to immunotherapy for tumor management, thereby potentially contributing to the favorable prognosis of cancer patients.