Targeting neddylation E2s: a novel therapeutic strategy in cancer

Zheng, Yi-Chao; Guo, Yan-Jia; Wang, Bo; Wang, Chong; Mamun, M. A. A.; Gao, Ya; Liu, Hong‐Min

doi:10.1186/s13045-021-01070-w

Cited by 32 publications

(32 citation statements)

References 133 publications

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“…Surprisingly, cofilin (K112R) and wild type (WT) cofilin in the presence of MLN4924 maintained their interactions with SSH1L, LIMK1, and CIN, as measured by co-precipitation with biotin-tagged cofilins. As mentioned previously, cofilin binds cooperatively to F-actin with severing occurring at the junctions between cofilin saturated and unbound regions [12,110]. In the presence of the neddylation inhibitor, F-actin binding of both cofilin (K112R) and WT cofilin increased.…”

Section: Ubiquitinylation and Neddylationmentioning

confidence: 54%

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Bamburg

Minamide

Wiggan

et al. 2021

Cells

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Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases.

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Section: Ubiquitinylation and Neddylationmentioning

confidence: 54%

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Bamburg

Minamide

Wiggan

et al. 2021

Cells

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“…Expanding the analysis to additional MPM cells, including at least two MPM for each histotype, one BAP1 + and one BAP1 - MPM, we found that MLN4924 decreased activity of UBE2M (Fig. 3 B), a component of the enzymatic system required for cullin 1 neddylation [ 22 ]. While MLN4924 impaired the neddylation/UBE2M system, it only slightly increased proteasome activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma

Belisario

Bironzo

Ananthanarayanan

et al. 2022

J Exp Clin Cancer Res

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Background The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. Methods Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. Results In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival. Conclusions We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.

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“…Increasing evidence suggests that neddylation is aberrantly activated in a wide range of tumor types, consequently affecting tumor progression and altering the TME ( Xie et al, 2021 ; Zhou et al, 2021 ). Further research on neddylation-related genes is warranted to provide new treatment strategies for cancer treatment ( Zheng et al, 2021 ). Lung cancer is one of the leading causes of human death worldwide and has a high incidence and mortality rate.…”

Section: Discussionmentioning

confidence: 99%

Neddylation pattern indicates tumor microenvironment characterization and predicts prognosis in lung adenocarcinoma

Cui

Chen

Pan

et al. 2022

Front. Cell Dev. Biol.

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Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a complex tumor microenvironment. Neddylation, as a type of post-translational modification, plays a vital role in the development of LUAD. To date, no study has explored the potential of neddylation-associated genes for LUAD classification, prognosis prediction, and treatment response evaluation.Methods: Seventy-six neddylation-associated prognostic genes were identified by Univariate Cox analysis. Patients with LUAD were classified into two patterns based on unsupervised consensus clustering analysis. In addition, a 10-gene prognostic signature was constructed using LASSO-Cox and a multivariate stepwise regression approach.Results: Substantial differences were observed between the two patterns of LUAD in terms of prognosis. Compared with neddylation cluster2, neddylation cluster1 exhibited low levels of immune infiltration that promote tumor progression. Additionally, the neddylation-related risk score correlated with clinical parameters and it can be a good predictor of patient outcomes, gene mutation levels, and chemotherapeutic responses.Conclusion: Neddylation patterns can distinguish tumor microenvironment and prognosis in patients with LUAD. Prognostic signatures based on neddylation-associated genes can predict patient outcomes and guide personalized treatment.

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Targeting neddylation E2s: a novel therapeutic strategy in cancer

Cited by 32 publications

References 133 publications

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma

Neddylation pattern indicates tumor microenvironment characterization and predicts prognosis in lung adenocarcinoma

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