CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Qian, Fengyuan; Tang, Tianjin; Wang, Yunlong; Wang, Bin; Wang, Lei; Shi, Hengliang

doi:10.4149/neo_2020_200414n399

neo

2021

DOI: 10.4149/neo_2020_200414n399

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CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Fengyuan Qian

Tianjin Tang

Yunlong Wang

et al.

Abstract: Our previous studies have illustrated that CacyBP/SIP (Calcyclin-binding protein or Siah-1-interacting protein) promoted the proliferation of glioma cells. However, the possible mechanism still needs to be clarified. In the current study, we aimed to uncover the potential mechanism of CacyBP/SIP in regulating glioma cell proliferation. We found that CacyBP/SIP decreased the protein level of p53, but not the mRNA level of p53 in p53 mutant U251 cell line, whereas, in p53 wild-type U87 cell line, CacyBP/SIP neit… Show more

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Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

Wang,

Zhang,

et al. 2023

J Exp Clin Cancer Res

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Background Despite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified. Methods The expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs). Results We identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy. Conclusions Our findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC.

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Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

Wang,

Zhang,

et al. 2023

J Exp Clin Cancer Res

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Impacts of Nutlin-3a and exercise on murine double minute 2–enriched glioma treatment

Chen,

Fan,

Luo

et al. 2024

Neural Regeneration Research

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JOURNAL/nrgr/04.03/01300535-202504000-00029/figure1/v/2024-07-06T104127Z/r/image-tiff Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role of the small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are the potential anti-cancer effects of SUMOylation. We used machine learning to create the exercise and SUMO-related gene signature (ESLRS). This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers. We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers, specifically highlighting how murine double minute 2 (MDM2), a component of the ESLRS, can be targeted by nutlin-3. This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation. Using comprehensive CRISPR screening, we validated the effects of specific ESLRS genes on low-grade glioma progression. We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation. Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway. Its efficacy decreased with MDM2 overexpression, and this was reversed by Nutlin-3a or exercise. Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation. Notably, both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells. These results suggest the potential for Nutlin-3a, an MDM2 inhibitor, with physical exercise as a therapeutic approach for glioma management. Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise, natural products, and immune regulation in cancer treatment.

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CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells

Cited by 2 publications

References 22 publications

Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

Impacts of Nutlin-3a and exercise on murine double minute 2–enriched glioma treatment

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