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松果菊苷下调skp2的表达抑制胶质母细胞瘤上皮间质转化及胶质瘤干细胞干性

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中南药学 2024年第3期22卷 626-632页

作者：吴振德王兆涛鞠其超张波厦门长庚医院神经外科福建厦门361028 广州医科大学附属第二医院神经外科广州560210

目的研究松果菊苷(ECH)对胶质母细胞瘤(GBM)的上皮间质转化(EMT)及其对GBM干细胞的影响,并探讨其分子机制。方法①体外实验:将GBM U87和U251细胞以0、5、10和20μmol·L^(-1) ECH浓度处理24 h。采用CCK-8法评估细胞活性;进行克隆形成实... 详细信息

目的研究松果菊苷(ECH)对胶质母细胞瘤(GBM)的上皮间质转化(EMT)及其对GBM干细胞的影响,并探讨其分子机制。方法①体外实验:将GBM U87和U251细胞以0、5、10和20μmol·L^(-1) ECH浓度处理24 h。采用CCK-8法评估细胞活性;进行克隆形成实验以测定克隆能力;通过Transwell实验评估迁移和侵袭能力;利用球形成实验评价GBM干细胞的成球能力;通过细胞免疫荧光检测干细胞标志物;使用Western blot分析EMT和干细胞相关蛋白表达。②体内实验:在裸鼠皮下注射U87细胞,每组5只。实验组腹腔注射ECH,对照组注射等体积溶剂。最后测定肿瘤体积、重量和体重,并用Western blot分析肿瘤中的skp2、EMT和干细胞相关蛋白表达。结果①体外实验显示,相较于0μmol·L^(-1) ECH组,10、20μmol·L^(-1) ECH处理显著降低了细胞活性(P20μmol·L^(-1) ECH组中克隆形成数量显著减少(Pskp2、EMT和干细胞特性相关蛋白表达在5、10μmol·L^(-1) ECH组中均显著降低(Pskp2、EMT(Vimentin、Snail)和干细胞标志物(Sox2、Nestin)的表达显著减少(P0.05)。结论ECH通过降低skp2表达抑制GBM的EMT和干细胞特性。

关键词：胶质母细胞瘤松果菊苷上皮间质转化干细胞干性 skp2

skp2 is a novel regulator of LSD1 expression and function in gastric cancer

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Genes & Diseases 2023年第6期10卷 2267-2269页

作者： Moges Dessale Asmamaw Li-Rong Zhang Hong-Min Liu Xiao-Jing Shi Ying Liu Department of Pharmacology School of Basic Medical SciencesState Key Laboratory for Esophageal Cancer Prevention and TreatmentZhengzhou UniversityZhengzhouHenan 450001China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhouHenan 450001China Key Laboratory of Advanced Drug Preparation Technologies Ministry of Education of ChinaZhengzhouHenan 450001China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Pharmacy The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Henan Engineering Research Center for Application&Translation of Precision Clinical Pharmacy ZhengzhouHenan 450052China

S-phase kinase-associated protein 2(skp2)is a well-characterized oncoprotein localized mainly in the nucleus and cytoplasm.It is an integral component of SCFskp2 E3 ubiquitin ligase complex which confers substrate selectivity to the ligase by specifically targeting a distinct set of proteins destined for proteasomal degradation such as p21,p27,cyclin E,and c-Myc.1 skp2 is crucial in a multitude of cellular processes including cell cycle,cell proliferation,apoptosis,differentiation,and survival.However,despite its immense and well-established role in ubiquitin-proteasome system-mediated protein turnover,much is unknown about the function of skp2 independent of the ubiquitination pathway.Previously,skp2 has been reported to regulate RhoA gene transcription and the p300 signaling pathway in an E3 ligase-independent manner.2Moreover,skp2 also acts as a cofactor for c-Myc-regulated gene expression.

关键词： skp2 expression. function

Chondroitin Polymerizing Factor (CHPF) promotes cell proliferation and tumor growth in human osteosarcoma by inhibiting skp2's ubiquitination while activating the AKT pathway

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Genes & Diseases 2023年第5期10卷 2125-2136页

作者： Yi Shen Jun Li Dan Peng Lele Liao Xia Chen Weiye Zhong Zicheng Liu Chao Yu Yuanliang Sun Department of Orthopaedics The Second Xiangya Hospital of Central South UniversityChangshaHunan 410000China Department of Spine Surgery Affiliated Hospital of Qingdao UniversityQingdaoShandong 266000China

Osteosarcoma is a common malignant tumor occurring in children and young adults. Chondroitin sulfate (CS) participates in cell adhesion, cell division, and the formation of neural networks in the body, the biosynthesis of which requires the participation of glycosyltransferases. CHPF, a glycosyltransferase, plays a role in the extension of CS. Recently, CHPF's biological roles and functional importance in human diseases including malignant tumors have been widely discussed. However, whether CHPF is involved in osteosarcoma development and growth has not been revealed. The present work aimed to investigate the expression levels, functional significance and molecular mechanism of CHPF in osteosarcoma progression. Our results revealed that CHPF is strongly expressed in osteosarcoma tissues and cells. Furthermore, CHPF serves as a tumor promoter in the development and progression of osteosarcoma through enhancing cell proliferation and migration while suppressing apoptosis. Exploration of the mechanism by which CHPF promotes osteosarcoma indicated that CHPF promotes osteosarcoma through counteracting skp2's ubiquitination and activating the Akt signaling pathway. For the first time, we clarified the roles of CHPF in osteosarcoma, and our results suggested that CHPF might be a novel therapeutic target in the treatment strategies for osteosarcoma.

关键词： Akt signaling pathway CHPF Osteosarcoma skp2 Ubiquitination

Novel roles of skp2 E3 ligase in cellular senescence,cancer progression,and metastasis

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癌症 2012年第4期31卷 169-177页

作者： Chia-Hsin Chan Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

S-phase kinase-associated protein 2 (skp2) belongs to the F-box protein family.It is a component of the SCF E3 ubiquitin ligase complex.skp2 has been shown to regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation,including cyclin-dependent kinase inhibitor p27.skp2 has also been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers.This review discusses the recent discoveries on the novel roles of skp2 in regulating cellular senescence,cancer progression,and metastasis,as well as the therapeutic potential of targeting skp2 for human cancer treatment.

关键词： skp2 p53 RhoA cellular senescence metastasis cancer therapy

Nobiletin downregulates the skp2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma

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Cancer Biology & Medicine 2021年第1期18卷 227-244页

作者： Tingting Chen Liu Liu Yonghong Zou Xiaoyan Hu Wenfeng Zhang Tao Zhou Xi Luo Weihua Fu Jie Xu Department of Urology Xinqiao Hospital of Army Medical UniversityChongqing 400037China Department of Nephrology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430040China Department of Reproductive Medicine Ji’an Central People’s HospitalJi'an 343100China Department of Infectious Disease the First Affiliated HospitalNanchang UniversityNanchang 330001China Department of Oncology Southwest Hospital of Army Medical UniversityChongqing 400038China

Objective:Natural extracts,including nobiletin,have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs.However,whether and how nobiletin affects tumor growth and progression in renal cell carcinoma(RCC)are still unclear.Methods:Cell proliferation,cell cycle and apoptosis analyses,colony-formation assays,immunoblotting analysis,and q RT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro.The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib.Results:Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells.Mechanistically,nobiletin decreased skp2 protein expression by reducing its transcriptional level.The downregulated skp2 caused accumulation of its substrates,p27 and p21,which further inhibited the activity of the G1 phase-related protein,CDK2,leading to inhibition of cell proliferation and tumor formation.A higher skp2 protein level indicated less sensitivity to the CDK4/6 inhibitor,palbociclib.A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model.Conclusions:Nobiletin downregulated the skp2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor,palbociclib,on RCC,which indicates a potential new therapeutic strategy.

关键词： Nobiletin skp2 palbociclib synergistic renal cell carcinoma

Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase skp2 in lung epithelial cells

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Frontiers of Medicine 2021年第2期15卷 252-263页

作者： Guizhen Wang Qun Zhao Hui Zhang Fan Liang Chen Zhang Jun Wang Zhenyin Chen Ran Wu Hong Yu Beibei Sun Hua Guo Ruie Feng Kaifeng Xu Guangbiao Zhou State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of Sciences&University of Chinese Academy of SciencesBeijing 100101China Hubei University of Medicine Shiyan 442000China Department of Pathology Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijing 100730China Department of Pulmonary and Critical Care Medicine Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijing 100730China Guizhou University School of Medicine Guiyang 550025China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%–18.5%of hospitalized adults,calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection.Here,we show that cigarette smoke extract(CSE)and carcinogen benzo(a)pyrene(BaP)increase ACE2 mRNA but trigger ACE2 protein catabolism.BaP induces an aryl hydrocarbon receptor(AhR)-dependent upregulation of the ubiquitin E3 ligase skp2 for ACE2 ubiquitination.ACE2 in lung tissues of non-smokers is higher than in smokers,consistent with the findings that tobacco carcinogens downregulate ACE2 in mice.Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells.Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and skp2 is an oncoprotein,tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.

关键词： SARS-CoV-2 tobacco smoke benzo(a)pyrene ACE2 skp2

ZNF292 suppresses proliferation of ESCC cells through ZNF292/skp2/P27 signaling axis

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Chinese Journal of Cancer Research 2021年第6期33卷 637-648页

作者： Wei Gong Jiancheng Xu Guangchao Wang Dan Li Qimin Zhan State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing 100142China

Objective:Increasing evidence has demonstrated that ZNF292 plays a suppressive role in cancer,however,little is known about its function and exact mechanism in esophageal squamous cell carcinoma(ESCC).Methods:Bioinformatic analysis and immunohistochemistry(IHC)were performed to analyze the role of ZNF292 in affecting the prognosis of ESCC.Cell proliferation and colony formation ability assays were performed to analyze cell growth after inferring the expression of ZNF292.Flow cytometry was used to analyze changes in the cell cycle upon the depletion of ZNF292.Quantitative real-time polymerase chain reaction(q RT-PCR)and western blot analysis were used to determine the alteration of cell cycle related RNAs and proteins after knocking down ZNF292.MG-132,cycloheximide(CHX)treatment experiments were performed to analyze the change and half-life time of P27 after knockdown of ZNF292.Chromatin immunoprecipitation(Ch IP)and luciferase reporter assays were used to analyze the transcriptional regulation of skp2 by ZNF292.Results:We report that low expression of ZNF292 is associated with poor prognosis,and ZNF292 emerges to be highly expressed in adjacent and normal tissues rather than tumor tissues in ESCC.Knockdown of ZNF292 significantly boosts cell growth and S phase entry in ESCC cells.ZNF292 depletion will decrease the expression and half-life time of P27,while knockdown of skp2 will result in elevated expression of P27.ZNF292 can bind to the promoter region of skp2,and knockdown of ZNF292 will boost the expression of skp2.Conclusions:Knockdown of ZNF292 mediates G1/S cell cycle procession by activating skp2/P27 signaling in ESCC cells.ZNF292 knockdown promotes skp2 expression at the transcriptional level,thereby boosting P27 ubiquitin-degradation,and eventually facilitating the S phase entrance.

关键词： ZNF292 cell cycle skp2 ESCC

Correlation of skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China

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Chinese Journal of Cancer 2011年第3期30卷 204-212页

作者： Hui-Min Xu Yi Liang Qiong Chen Qi-Nian Wu Yun-Miao Guo Guo-Ping Shen Ru-Hua Zhang Zhi-Wei He Yi-Xin Zeng Fang-Yun Xie Tie-Bang Kang State Key Laboratory of Oncology in South China Guangzhou Guangdong 510060 P. R. China Department of Radiation Oncology Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China Department of Experimental Research Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China Department of Pathology Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China iuangdong Medical College Cancer Center Dongguan Guangdong 523808 P. R. China.

S-phase kinase-associated protein 2 (skp2), which plays a role in cell cycle regulation, is commonly overexpressed in a variety of human cancers and associated with poor prognosis. However, its role in nasopharyngeal carcinoma (NPC) is not well understood. In this study, we examined the clinical significance of skp2, with a particular emphasis on overall survival (OS) and disease-free survival (DFS), in NPC cases in South China, where NPC is an epidemic. Additionally, we explored the function of skp2 in maintaining a cancer stem cell -like phenotype in NPC cell lines. skp2 expression was assessed for 127 NPC patients using tissue microarrays and immunohistochemistry and analyzed together with clinicopathologic features, OS, and DFS. skp2 expression was detectable, or positive, in 75.6% of patients. Although there was no correlation between skp2 and any clinicopathologic factor, skp2 expression significantly portended inferior OS (P = 0.013) and DFS (P = 0.012). In the multivariate model, skp2 expression remained significantly predictive of poor OS [P = 0.009, risk ratio (RR) = 4.06] and DFS (P = 0.008, RR = 3.56), and this was also true for clinical stage (P = 0.012 and RR=3.201 for OS; P = 0.002 and RR=1.94 for DFS) and sex (P = 0.016 and RR=0.31 for OS; P = 0.006 and RR = 0.27 for DFS). After skp2 knockdown, a colony formation assay was used to evaluate the self-renewal property of stem-like cells in the NPC cell lines CNE-1 and CNE-2. The colony formation efficiency in CNE-1 and CNE-2 cells was decreased. In skp2-transfected CNE-1 and CNE-2 cells, side population (SP) proportion was increased as detected by flow cytometry. skp2 is an independent prognostic marker for OS and DFS in NPC. skp2 may play a role in maintaining the cancer stem cell-like phenotype of NPC cell lines.

关键词： skp2 蛋白表达鼻咽癌预后患者中国全国人民代表大会细胞周期调控

Regulation of skp2 protein stability by heat shock protein 90 chaperone machinery

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Signal Transduction and Targeted Therapy 2021年第8期6卷 2331-2333页

作者： Lili Cai Lihui Li Xihui Chen Lijun Jia Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina

Dear Editor,S phase kinase-associated protein 2(skp2),a substrate recognition component of the SCFskp2 ubiquitin ligase complex,plays an oncogenic role in tumorigenesis by targeting a variety of tumor suppressors(e.g.,p21,p27,and p130)for ubiquitina-tion and subsequent degradation.1 As a well-characterized oncoprotein,the aberrant expression and dysregulation of skp2 are frequently observed in different human cancers.Given its critical role in governing tumorigenesis and progression,skp2 has emerged as a potential pharmacological target for anticancer therapy.

关键词： skp2 suppressor shock