组蛋白去乙酰酶SIRT1介导细胞自噬在肿瘤中的研究进展

自噬现象广泛存在于真核细胞中,是细胞的一种自我保护机制。这类分解代谢过程发生在细胞内,进化上具有高度保守性,在多种疾病及生命进程中发挥着重要作用。Sirtuin1（SIRT1）是一种组蛋白去乙酰化酶,具有烟酰胺腺嘌呤二核苷酸（NAD+）依赖性,在细胞生存、衰老、凋亡和代谢等生物学过程中扮演着重要角色。近年来,SIRT1与自噬的关系受到越来越多的关注,且SIRT1被证明与肿瘤的发生发展密切相关。探索SIRT1和自噬间的联系以及SIRT1介导的细胞自噬在肿瘤中的作用,有助于对肿瘤的发生发展机制展开进一步的探索。本文对肿瘤中SIRT1与自噬的作用关系及机制作以综述,希望能够为肿瘤的深入研究及新型靶向药物的研制提供新思路。     

SIRT3抗癌变作用的研究进展

目的:总结沉默信息调节因子3(SIRT3)与肿瘤的关系,探讨SIRT3在抗肿瘤发生方面的作用。方法:应用Medline、PubMed及CNKI期刊全文数据库检索系统,以"沉默信息调节因子3"、"肿瘤"为关键词,检索2005-01-2011-10的相关文献。纳入标准:1)SIRT3的作用;2)SIRT3与肿瘤发生的关系。分析文献29篇。结果:SIRT3是一个重要的线粒体去乙酰化酶。对肿瘤的发生有抑制作用,其作用机制一定程度上与抑制线粒体内ROS增高有关,为临床上肿瘤的早期发现和治疗起到一定的理论指导作用。ITR3也参与对细胞代谢和生存的调节。结论:SIRT3有抑制肿瘤发生的作用,为临床上肿瘤的早期发现和治疗起到一定的理论指导作用,将为肿瘤的治疗提供新的策略和方法。     

沉默信息调节因子1在肿瘤发生发展中的作用

沉默信息调节因子1（SIRT1）是一种依赖于烟酰胺腺嘌呤二核苷酸的组蛋白脱乙酰酶,参与肿瘤的发生发展过程。研究表明,SIRT1在胃癌、乳腺癌、前列腺癌等多种实体肿瘤中呈高表达,可促进肿瘤发生发展;同时发现,SIRT1在其他肿瘤如胶质母细胞瘤、膀胱癌、卵巢癌等中SIRT1表达降低,起抑癌基因的作用。因此,SIRT1的具体作用机制仍未阐明,尚存争议。     

沉默信息调节因子1与肿瘤耐药相关研究进展

沉默信息调节因子1(sirtuin 1,SIRT1)是一种依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的组蛋白脱乙酰酶,主要参与组蛋白的共价修饰,并可通过转录、翻译及翻译后修饰等多种途径参与肿瘤的发生、发展过程。获得性耐药使肿瘤细胞产生耐药性,现已成为癌症治疗所面临的严峻挑战。本文概述了SIRT1与肿瘤耐药密切相关的一些研究进展,为癌症治疗提供新思路和新方向。     

蛋白磷酸酶4催化亚基在肿瘤进展中的作用

蛋白磷酸酶4(protein phosphatase 4,PP4)是一种进化保守的蛋白质丝氨酸/苏氨酸磷酸酶,以蛋白磷酸酶4催化亚基（protein phosphatase catalytic 4,PP4C）与不同的调节亚基相结合组成多聚体的形式存在并发挥功能。PP4C主要参与包括细胞葡萄糖代谢、细胞信号传导通路、DNA损伤反应、细胞周期、细胞增殖和肿瘤发生、迁移等多种细胞生物学过程。近年来,随着对PP4C的研究越来越广泛,已证明其在多种恶性肿瘤的发展和进展中起重要作用,有望成为肿瘤生物标志物和肿瘤治疗的靶标。本文就PP4C参与多种细胞生物学过程及其在肿瘤的发生和进展过程中的作用进行综述。     

LincRNA-p21在癌症机制中的研究进展CSCD

长链非编码RNA是一类不编码蛋白质的RNA,通过多种机制参与不同的生物学行为。lincRNA-p21是一种抑癌基因,并与p53密切相关。lincRNA-p21通过MDM2、ING1b和p21等多个靶标调节p53参与细胞周期、增殖、凋亡的调控,并通过HIF-1α协调Warburg效应参与细胞代谢等多种生物学作用。lincRNA-p21与肿瘤的预后和治疗密切相关。因此lincRNA-p21可作为癌症的诊断和预后的生物标志物。本文就lincRNA-p21生物学功能与在疾病中的作用机制作一简要综述。     

甲基转移酶样蛋白14与肿瘤

N6-甲基腺嘌呤(m6A)修饰是最常见的RNA表观遗传修饰, 其在恶性肿瘤发生发展过程中扮演重要角色。甲基转移酶样蛋白14(METTL14)是催化m6A修饰的主要甲基化酶之一, 参与调节RNA剪接、翻译及降解等生物学进程。最新研究表明METTL14不仅通过多种分子机制调控肿瘤生长、侵袭和转移, 而且其表达水平与肿瘤患者预后及抗肿瘤治疗效果密切相关。深入了解METTL14在乳腺癌、消化系统肿瘤及泌尿系统肿瘤中的作用机制, 有助于为基于m6A修饰的肿瘤防治提供新的临床标志物及药物治疗靶点。     

FABP5在肿瘤中作用及机制的研究进展

脂肪酸结合蛋白5(fatty acid binding protein 5,FABP5)是脂肪酸结合蛋白家族之一,在调控脂肪酸的摄取、运输和代谢中发挥重要作用。近年来多项研究证实,FABP5在多种肿瘤中高表达,其参与了肿瘤的增殖、转移以及诱导免疫逃逸等多种肿瘤生物学过程。该文综述了FABP5在肿瘤中的最新研究进展,旨在讨论FABP5在肿瘤中的作用及机制,为肿瘤相关研究提供新思路,同时为肿瘤新靶点的开发提供更多理论依据。     

Chemerin在代谢综合征相关肿瘤治疗中的作用及机制

代谢综合征是一组以胰岛素抵抗为核心，多种代谢异常簇集发生在同一个体的临床状态，与许多恶性肿瘤的发生有关。脂肪组织可分泌大量脂肪因子，参与代谢综合征及其相关肿瘤的发生发展。Chemerin是近年新确认的脂肪因子，具有促进脂肪分化和炎症反应、影响胰岛素抵抗及调节脂代谢等作用，参与代谢综合征极其相关疾病的进程。此外，作为一种趋化因子，Chemerin可介导肿瘤微环境中多种免疫细胞募集，发挥抗肿瘤作用。本文将针对Chemerin在代谢综合征相关肿瘤治疗中的作用及机制进行综述。     

血红素加氧酶-1与肿瘤的研究进展

血红素加氧酶-1(HO-1)是一种重要的抗炎、抗凋亡、抗氧化及耐药相关基因。在生理状态下,人体正常组织中的HO-1蛋白呈低表达。在遭受酒精、辛辣及热烫等持续刺激时,其表达升高。HO-1的表达异常与肿瘤的生物学行为密切相关。近年来研究发现,其基因多态性及分解血红素产生的代谢产物(胆红素、Fe²⁺、CO)参与的多条信号通路的激活,并影响多种肿瘤疾病的发生、发展。另外,在许多肿瘤中HO-1表达水平上调,不仅影响肿瘤微环境中氧化应激水平对肿瘤细胞生长及增殖的调节,而且还能诱导肿瘤细胞产生耐药性。因此,HO-1表达异常可能参与了肿瘤的发生发展。     

Emerging role of SIRT2 in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most devastating cancer types, accounting for >80% of lung cancer cases. The median relative survival time of patients with NSCLC is <1 year. Lysine acetylation is a major post-translational modification that is required for various biological processes, and abnormal protein acetylation is associated with various diseases, including NSCLC. Protein deacetylases are currently considered cancer permissive partly due to malignant cells being sensitive to deacetylase inhibition. Sirtuin 2 (SIRT2), a primarily cytosolic nicotinamide adenine dinucleotide-dependent class III protein deacetylase, has been shown to catalyze the removal of acetyl groups from a wide range of proteins, including tubulin, ribonucleotide reductase regulatory subunit M2 and glucose-6-phosphate dehydrogenase. In addition, SIRT2 is also known to possess lysine fatty deacylation activity. Physiologically, SIRT2 serves as a regulator of the cell cycle and of cellular metabolism. It has been shown to play important roles in proliferation, migration and invasion during carcinogenesis. It is notable that both oncogenic and tumor suppressive functions of SIRT2 have been described in NSCLC and other cancer types, suggesting a context-specific role of SIRT2 in cancer progression. In addition, inhibition of SIRT2 exhibits a broad anticancer effect, indicating its potential as a therapeutic for NSCLC tumors with high expression of SIRT2. However, due to the diverse molecular and genetic characteristics of NSCLC, the context-specific function of SIRT2 remains to be determined. The current review investigated the functions of SIRT2 during NSCLC progression with regard to its regulation of metabolism, stem cell-like features and autophagy.     

SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation

The deacetylase SIRT1 regulates multiple biological processes including cellular metabolism and aging. Importantly, SIRT1 can also inactivate the p53 tumor suppressor via deacetylation, suggesting a role in oncogenesis. Recently, SIRT1 was shown to be released from its endogenous inhibitor DBC1 by a process requiring AMPK and the phosphorylation of SIRT1 by yet undefined kinase(s). Here we provide further evidence that AMPK directly phosphorylates SIRT1 on T344, releasing it from DBC1. Furthermore, a phospho-mimetic SIRT1 (T334E) showed decreased binding to DBC1, supporting the importance of this phosphorylation in AMPK-mediated regulation of SIRT1 activity. In addition, inhibition of AMPK by Compound C led to increased p53 acetylation, suggesting a role for the AMPK/SIRT1 pathway in regulating p53 signaling. Together, our results support a hypothesis that AMPK negatively regulates p53 acetylation via phosphorylation of SIRT1 on T344. Furthermore, our findings also define the AMPK/SIRT1 axis as a possible targetable pathway to regulate p53 function.     

Recent advances of SIRT1 and implications in chemotherapeutics resistance in cancer

Cancer is a big group of diseases and one of the leading causes of mortality worldwide. Despite enormous studies and efforts are being carried out in understanding the cancer and developing drugs against tumorigenesis, drug resistance is the main obstacle in cancer treatments. Chemotherapeutic treatment is an important part of cancer treatment and drug resistance is getting gradually multidimensional with the advancement of studies in cancer. The underlying mechanisms of drug resistance are largely unknown. Sirtuin1 (SIRT1) is a type of the Class III histone deacetylase family that is distinctively dependent on nicotinamide adenine dinucleotide (NAD+) for catalysis reaction. SIRT1 is a molecule which upon upregulation directly influences tumor progression, metastasis, tumor cell apoptosis, autophagy, DNA repair, as well as other interlinked tumorigenesis mechanism. It is involved in drug metabolism, apoptosis, DNA damage, DNA repair, and autophagy, which are key hallmarks of drug resistance and may contribute to multidrug resistance. Thus, understanding the role of SIRT1 in drug resistance could be important. This study focuses on the SIRT1 based mechanisms that might be a potential underlying approach in the development of cancer drug resistance and could be a potential target for drug development.     

Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1

Investigating existing drugs for repositioning can enable overcoming bottlenecks in the drug development process. Here, we investigated the effect and molecular mechanism of the antipsychotic drug chlorpromazine (CPZ) and identified its potential for treating colorectal cancer (CRC). Human CRC cell lines harboring different p53 statuses were used to investigate the inhibitory mechanism of CPZ. CPZ effectively inhibited tumor growth and induced apoptosis in CRC cells in a p53-dependent manner. Activation of c-jun N-terminal kinase (JNK) was crucial for CPZ-induced p53 expression and the subsequent induction of tumor apoptosis. Induction of p53 acetylation at lysine382 was involved in CPZ-mediated tumor apoptosis, and this induction was attenuated by sirtuin 1 (SIRT1), a class III histone deacetylase. By contrast, knocking down SIRT1 sensitized tumor cells to CPZ treatment. Moreover, CPZ induced the degradation of SIRT1 protein participating downstream of JNK, and JNK suppression abrogated CPZ-mediated SIRT1 downregulation. Clinical analysis revealed a significant association between high SIRT1 expression and poor outcome in CRC patients. These data suggest that SIRT1 is an attractive therapeutic target for CRC and that CPZ is a potential repositioned drug for treating CRC.     

Deacetylation of cortactin by SIRT1 promotes cell migration

Cortactin binds F-actin and promotes cell migration. We showed earlier that cortactin is acetylated. Here, we identify SIRT1 (a class III histone deacetylase) as a cortactin deacetylase and p300 as a cortactin acetylase. We show that SIRT1 deacetylates cortactin in vivo and in vitro and that the SIRT1 inhibitor EX-527 increases amounts of acetylated cortactin in ovarian cancer cells. We also show that p300 acetylates cortactin in vivo and that cells lacking or depleted of p300 express less-acetylated cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of cortactin to its repeat region, which also binds F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2alpha (the mouse homolog of SIRT1) migrated more slowly than did wild-type cells. The expression of SIRT1 in sir2alpha-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of cortactin. SIRT1 and cortactin were more abundant in breast tumor tissue than in their normal counterparts, whereas SIRT1 expression inversely correlates with the ratio of acetylation cortactin versus total cortactin. These data suggest that deacetylation of cortactin is associated with high levels of SIRT1 and tumorigenesis. Finally, breast and ovarian cancer cell lines expressing an acetylation mimetic mutant of cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that cortactin is a novel substrate for SIRT1 and p300 and, for the first time, a possible role for SIRT1 in cell motility through deacetylation of cortactin.     

High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+) -dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.