Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer:A systematic review

BACKGROUND Colorectal cancer(CRC)is the third most frequent and the second most fatal cancer.The search for more effective drugs to treat this disease is ongoing.A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies.Ubiquitin-specific peptidases(USPs),the largest group of the deubiquitinase protein family,have long been implicated in various cancers.There have been numerous studies on the role of USPs in CRC;however,a comprehensive view of this role is lacking.AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC.METHODS We systematically queried the MEDLINE(via PubMed),Scopus,and Web of Science databases.RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC:Regulation of the cell cycle,apoptosis,cancer stemness,epithelial–mesenchymal transition,metastasis,DNA repair,and drug resistance.The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC.The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms.CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

非小细胞肺癌组织中组蛋白去乙酰化酶7、泛素特异性肽酶10的表达变化及其意义

目的观察非小细胞肺癌(NSCILC)组织中组蛋白去乙酰化酶7(HDAC7)、泛素特异性肽酶10(USP10)的表达变化,探讨其意义。方法98例NSCLC患者,均行肿瘤切除术,术中保留癌组织及癌旁组织。采用免疫组织化学法检测癌组织及癌旁组织HDAC7、USP10,采用Spearman相关性分析法分析NSCLC癌组织中HDAC7与USP10表达的相关性,分析HDAC7、USP10表达与NSCLC患者临床病理参数的关系,采用Kaplan-Meier生存曲线分析HDAC7、USP10表达与NSCLC患者预后的关系,采用COX多因素比例风险模型分析NSCLC患者预后的影响因素。结果NSCLC组织、癌旁组织中HDAC7阳性率分别为65.31%(64/98)、6.12%(6/98)(χ^(2)=74.756,P<0.05);NSCLC组织、癌旁组织中USP10阳性率分别为63.27%(62/98)、8.16%(8/98)(χ^(2)=64.800,P<0.05)。肿瘤低分化程度、有淋巴结转移及TNM分期Ⅲ期NSCLC癌组织HDAC7,USP10表达阳性率高于高中分化程度、无淋巴结转移及TNM分期Ⅰ~Ⅱ期(P均<0.05)。NSCLC组织中HDAC7、USP10的表达呈正相关(r=0.714,P<0.05)。与表达阴性者比较,HDAC7、USP10表达阳性的患者3年累积生存率低(χ^(2)=16.300、15.870,P均<0.05)。HDAC7表达阳性、USP10表达阳性、肿瘤低分化程度、有淋巴结转移、TNM分期Ⅲ期是NSCLC患者预后的独立危险因素。结论NSCLC癌组织中HDAC7、USP10高表达,HDAC7、USP10可能协同促进NSCLC的发生发展,HDAC7、USP10高表达NSCLC患者的预后较差。

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

Background:Melatonin,a natural hormone secreted by the pineal gland,has been reported to exhibit antitumor properties through diverse mechanisms of action.However,the oncostatic function of melatonin on esophageal squamous cell carcinoma(ESCC) remains elusive.This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.Methods:ESCC cell lines treated with or without melatonin were used in this study.In vitro colony formation and 5-Ethynyl-2’-deoxyuridine(EdU) incorporation assays,and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells.RNA-seq,qPCR,Western blotting,recombinant lentivirus-mediated target gene overexpression or knockdown,plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth.IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC.Results:Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7(HDAC7),c-Myc and ubiquitin-specific peptidase 10(USP10) in ESCC cells(P<0.05).The expressions of HDAC7,c-Myc and USP10 in tumors were significantly higher than the paired normal tissues from 148 ESCC patients(P<0.001).Then,the Kaplan-Meier survival analysis suggested that ESCC patients with high HDAC7,c-Myc or USP10levels predicted worse overall survival(log-rank P<0.001).Co-IP and Western blotting further revealed that HDAC7physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription.Notably,our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth,and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells.Additionally,we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.Conclusions:Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth,and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia-reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination

Despite complications were significantly reduced due to the popularity of percutaneous coronary intervention(PCI) in clinical trials, reperfusion injury and chronic cardiac remodeling significantly contribute to poor prognosis and rehabilitation in AMI patients. We revealed the effects of HSP47 on myocardial ischemia-reperfusion injury(IRI) and shed light on the underlying molecular mechanism.We generated adult mice with lentivirus-mediated or miRNA(mi1/133TS)-aided cardiac fibroblastselective HSP47 overexpression. Myocardial IRI was induced by 45-min occlusion of the left anterior descending(LAD) artery followed by 24 h reperfusion in mice, while ischemia-mediated cardiac remodeling was induced by four weeks of reperfusion. Also, the role of HSP47 in fibrogenesis was evaluated in cardiac fibroblasts following hypoxia-reoxygenation(HR). Extensive HSP47 was observed in murine infarcted hearts, human ischemic hearts, and cardiac fibroblasts and accelerated oxidative stress and apoptosis after myocardial IRI. Cardiac fibroblast-selective HSP47 overexpression exacerbated cardiac dysfunction caused by chronic myocardial IRI and presented deteriorative fibrosis and cell proliferation.HSP47 upregulation in cardiac fibroblasts promoted TGFβ1-Smad4 pathway activation and Smad4 deubiquitination by recruiting ubiquitin-specific peptidase 10(USP10) in fibroblasts. However, cardiac fibroblast specific USP10 deficiency abolished HSP47-mediated fibrogenesis in hearts. Moreover, blockage of HSP47 with Col003 disturbed fibrogenesis in fibroblasts following HR. Altogether, cardiac fibroblast HSP47 aggravates fibrosis post-myocardial IRI by enhancing USP10-dependent Smad4 deubiquitination,which provided a potential strategy for myocardial IRI and cardiac remodeling.

Kallikrein-related peptidases 6 and 10 are elevated in cerebrospinal fluid of patients with Alzheimer’s disease and associated with CSF-TAU and FDG-PET

Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.

二肽基肽酶-4抑制剂治疗小鼠溃疡性结肠炎的机制

目的:初步探讨二肽基肽酶-4(dipeptidylpeptidase-4,DPP-4)抑制剂治疗小鼠溃疡性结肠炎(ulcerative colitis,UC)的作用机制.方法:将30只♂Balb/c小鼠随机分为空白对照组、模型对照组、DPP-4抑制剂治疗组、柳氮磺砒啶(sulfasalazine,SASP)治疗组、DPP-4抑制剂和SASP联合治疗组.除空白对照组外,其余各组用5%葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导小鼠UC模型,空白对照组和模型对照组给予0.5%羧甲基纤维素(carboxymethyl cellulose,CMC)灌胃,DPP-4抑制剂组、SASP组、联合治疗组分别给予西格列汀、SASP及两者联合灌胃治疗,1次/d,每天记录小鼠疾病活动指数(disease activity index,DAI)值,6 d后处死小鼠,分离结肠组织,进行病理组织学观察,检测结肠组织髓过氧化物酶(myeloperoxidase,MPO)活性,采用ELISA法测定小鼠血清肿瘤坏死因子-(tumor necrosis factor-,TNF-)、白介素-10(interleukin-10,IL-10)、胰高血糖素样肽-2(glucagon-like peptid-2,GLP-2)水平.结果:与模型对照组MPO活性(1.81 U/g±0.23 U/g)相比,DPP-4抑制剂组(1.20 U/g±0.19 U/g)、SASP组(0.96 U/g±0.07 U/g)、联合治疗组(0.81 U/g±0.06 U/g)MPO活性均显著降低(P<0.01);与模型对照组血清TNF-水平(106.86 ng/L±17.02 ng/L)相比,DPP-4抑制剂组(81.24 ng/L±9.12 ng/L)、SASP组(67.86 ng/L±9.32 ng/L)、联合治疗组(53.37ng/L±9.08 ng/L)血清TNF-水平均显著降低(P<0.01);与模型对照组血清GLP-2水平(33.10pmol/L±3.22 pmol/L)相比,DPP-4抑制剂组(55.07 pmol/L±4.43 pmol/L)及联合治疗组(58.07 pmol/L±5.43 pmol/L)血清GLP-2水平显著升高(P<0.01);与模型对照组血清IL-10水平(38.20 pg/mL±2.61 pg/mL)相比,SASP组(58.10 pg/mL±2.72 pg/mL)及联合治疗组(60.68 pg/mL±2.35 pg/mL)血清IL-10水平显著升高(P<0.01).结论:DPP-4抑制剂通过抗炎和升高血清GLP-2水平,达到修复结肠炎黏膜损伤的作用,其抗炎机制与SASP作用机制不同,DPP-4抑制剂与SASP联合用药在治疗小鼠UC方面存在协同作用.

Notoginsenoside Ft1 inhibits colorectal cancer growth by increasing CD8^(+)T cell proportion in tumor-bearing mice through the USP9X signaling pathway

The management of colorectal cancer(CRC)poses a significant challenge,necessitating the development of innovative and effective therapeutics.Our research has shown that notoginsenoside Ft1(Ng-Ft1),a small molecule,markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8^(+)T cells in tumor-bearing mice,thus restraining tumor growth.Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X,undermining its role in shieldingβ-catenin.This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway.These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC,working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8^(+)T cell prevalence within the tumor environment.