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UBE2S facilitates glioblastoma progression through activation of the NF-κB pathway via attenuating K11-linked ubiquitination of AKIP1

文献类型： 外文期刊

作者： Han, Zhibin 1 ; Xu, Lin 1 ; Wang, Aowen 1 ; Wang, Baoju 2 ; Liu, Qinfang 3 ; Liu, Hongyang 4 ; Liu, Qi 5 ; Gang, Zhenbo 1 ; Yu, Shengkun 6 ; Mu, Long 7 ; Weng, Changjiang 4 ; Lin, Zhiguo 1 ; Hu, Li 1 ;

作者机构： 1.Harbin Med Univ, Dept Neurosurg, Affiliated Hosp 1, Harbin, Peoples R China

2.Harbin Med Univ, Dept Gynecol, Affiliated Hosp 1, Harbin, Peoples R China

3.Yale Univ, Sch Med, Dept Neurosci, New Haven, CT USA

4.Chinese Acad Agr Sci, State Key Lab Vet Biotechnol, Harbin Vet Res Inst, Harbin, Peoples R China

5.Harbin Med Univ, Dept Pathol, Affiliated Hosp 1, Harbin, Peoples R China

6.Nanjing Med Univ, Dept Neurosurg, Affiliated Hosp 4, Nanjing, Peoples R China

7.Shandong First Med Univ, Dept Neurosurg, Affiliated Hosp 1, Jinan, Peoples R China

8.Shandong Prov Qianfoshan Hosp, Jinan, Peoples R China

关键词： GBM; UBE2S; AKIP1; Deubiquitination; NF-kappa B

期刊名称：INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES （ 影响因子：7.7； 五年影响因子：7.7 ）

ISSN： 0141-8130

年卷期： 2024 年 278 卷

页码：

收录情况： SCI

摘要： Background: Rapid proliferation is a hallmark of glioblastoma multiforme (GBM) and a major contributor to its recurrence. Aberrant ubiquitination has been implicated in various diseases, including cancer. In our preliminary studies, we identified Ubiquitin-conjugating enzyme E2S (UBE2S) as a potential glioma biomarker, exhibiting close associations with glioma grade and protein phosphatase 1, regulatory subunit 105 (Ki67) expression levels. However, the underlying molecular mechanisms remained elusive. NF-kappa B is an important signaling pathway that promotes GBM proliferation. Direct intervention targeting NF-kappa B has not yielded the expected results, prompting the exploration of new molecules for regulating NF-kappa B as a new direction. Methods: This study employed methods including yeast two-hybrid and immunoprecipitation to uncover the interaction between UBE2S and A kinase interacting protein 1 (AKIP1). Laser confocal microscopy was used to observe the localization of UBE2S and AKIP1. Dual luciferase reporter genes were utilized to observe the activation of NF-kappa B. Results: Our findings demonstrate that UBE2S deficiency significantly impedes GBM progression, both in vitro and in vivo. Mechanistically, UBE2S plays a crucial role in recruiting Ubiquitin Specific Peptidase 15 (USP15), facilitating the removal of K11-linked ubiquitination on AKIP1. This action enhances AKIP1 stability within the GBM context. The resulting increase in AKIP1 levels further augments nuclear factor kappa-B (NF-kappa B) transcriptional activity, leading to the upregulation of downstream genes regulated by the NF-kappa B pathway, thereby promoting GBM progression. Conclusions: In summary, our findings reveal the role of the UBE2S/AKIP1-NF-kappa B axis in regulating GBM progression and provide novel evidence supporting UBE2S as a potential drug target for GBM.

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