Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?

Yu, Qing; Sun, Yi

doi:10.2147/dddt.s286373

Cited by 6 publications

(5 citation statements)

References 65 publications

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“…In our and others' previous study [25][26][27][28], Neddylation inhibitor MLN4924 has significant anti-tumor effect in both vitro and vivo. Through TCGA database and KEGG analysis, we found that NEED8, an important molecule in the Neddylation pathway, as well as the catalytic enzymes UBE2M and UBE2F, were all transcribed at higher levels in USML tissues than NL tissues (Fig.…”

Section: Correlation Between Hub Genes and Neddylation Pathwaymentioning

confidence: 62%

Identification of uterine leiomyosarcoma-associated hub genes and immune cell infiltration pattern using weighted co-expression network analysis and CIBERSORT algorithm

et al. 2021

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Background While large-scale genomic analyses symbolize a precious attempt to decipher the molecular foundation of uterine leiomyosarcoma (ULMS), bioinformatics results associated with the occurrence of ULMS based totally on WGCNA and CIBERSORT have not yet been reported. This study aimed to screen the hub genes and the immune cell infiltration pattern in ULMS by bioinformatics methods. Methods Firstly, the GSE67463 dataset, including 25 ULMS tissues and 29 normal myometrium (NL) tissues, was downloaded from the public database. The differentially expressed genes (DEGs) were screened by the ‘limma’ package and hub modules were identified by weighted gene co-expression network analysis (WGCNA). Subsequently, gene function annotations were performed to investigate the biological role of the genes from the intersection of two groups (hub module and DEGs). The above genes were calculated in the protein–protein interaction (PPI) network to select the hub genes further. The hub genes were validated using external data (GSE764 and GSE68295). In addition, the differential immune cell infiltration between UL and ULMS tissues was investigated using the CIBERSORT algorithm. Finally, we used western blot to preliminarily detect the hub genes in cell lines. Results WGCNA analysis revealed a green-yellow module possessed the highest correlation with ULMS, including 1063 genes. A total of 172 DEGs were selected by thresholds set in the ‘limma’ package. The above two groups of genes were intersected to obtain 72 genes for functional annotation analysis. Interestingly, it indicated that 72 genes were mainly involved in immune processes and the Neddylation pathway. We found a higher infiltration of five types of cells (memory B cells, M0-type macrophages, mast cells activated, M1-type macrophages, and T cells follicular helper) in ULMS tissues than NL tissues, while the infiltration of two types of cells (NK cells activated and mast cells resting) was lower than in NL tissues. In addition, a total of five genes (KDR, CCL21, SELP, DPT, and DCN) were identified as the hub genes. Internal and external validation demonstrated that the five genes were over-expressed in NL tissues compared with USML tissues. Finally, the correlation analysis results indicate that NK cells activated and mast cells activated positively correlated with the hub genes. However, M1-type macrophages had a negative correlation with the hub genes. Moreover, only the DCN may be associated with the Neddylation pathway. Conclusion A series of evidence confirm that the five hub genes and the infiltration of seven types of immune cells are related to USML occurrence. These hub genes may affect the occurrence of USML through immune-related and Neddylation pathways, providing molecular evidence for the treatment of USML in the future.

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Section: Correlation Between Hub Genes and Neddylation Pathwaymentioning

confidence: 62%

Identification of uterine leiomyosarcoma-associated hub genes and immune cell infiltration pattern using weighted co-expression network analysis and CIBERSORT algorithm

et al. 2021

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“…Many NAE inhibitors have been reported thereafter (for review, see refs. 31 , 32 ), including one from our group recently. 17 The most significant one, TAS4464, 33 – 35 has completed the phase I clinical trial recently in patients with advanced solid tumors but discontinued due to liver toxicity.…”

Section: Discussionmentioning

confidence: 99%

“… 38 Finally, our group has recently reported that gossypol has some inhibitory activity against cullin neddylation by targeting the complex of SAG-CUL5 and RBX1-CUL1. 15 , 32 However, there is no report on small molecule inhibitors targeting UBE2F so far.…”

Section: Discussionmentioning

confidence: 99%

A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer

et al. 2022

Sig Transduct Target Ther

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Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.

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“…To discover potent and novel inhibitors targeting Cul5 neddylation, Sun's group screened a library of 17,000 molecules using an AlphaScreen-based assay, yielding the natural 53 (gossypol) as a potent inhibitor of cullin neddylation (Figure 24 ) 228 , 229 . Molecule 53 effectively inhibited the neddylation of Cul5 and Cul1 with the IC 50 values of 4.3 and 3.4 μM, respectively.…”

Section: Inhibitors Of Neddylation Enzymesmentioning

confidence: 99%

“…To discover potent and novel inhibitors targeting Cul5 neddylation, Sun's group screened a library of 17,000 molecules using an AlphaScreenbased assay, yielding the natural 53 (gossypol) as a potent inhibitor of cullin neddylation (Figure 24) [228,229]…”

Section: Cullin 1/5 Inhibitorsmentioning

confidence: 99%

Targeting cullin neddylation for cancer and fibrotic diseases

He,

Yang,

Zengyangzong

et al. 2023

Theranostics

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Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.

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Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?

Cited by 6 publications

References 65 publications

Identification of uterine leiomyosarcoma-associated hub genes and immune cell infiltration pattern using weighted co-expression network analysis and CIBERSORT algorithm

Identification of uterine leiomyosarcoma-associated hub genes and immune cell infiltration pattern using weighted co-expression network analysis and CIBERSORT algorithm

A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer

Targeting cullin neddylation for cancer and fibrotic diseases

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