更新于：2024-05-01

SET

SET nuclear proto-oncogene

更新于：2024-05-01

基本信息

别名

2PP2A、HLA-DR-associated protein II、I-2PP2A

+ [11]

简介

Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning. Isoform 2 anti-apoptotic activity is mediated by inhibition of the GZMA-activated DNase, NME1. In the course of cytotoxic T-lymphocyte (CTL)-induced apoptosis, GZMA cleaves SET, disrupting its binding to NME1 and releasing NME1 inhibition. Isoform 1 and isoform 2 are potent inhibitors of protein phosphatase 2A. Isoform 1 and isoform 2 inhibit EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) and nucleosomes, most probably by masking the accessibility of lysines of histones to the acetylases. The predominant target for inhibition is histone H4. HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA. Both isoforms stimulate DNA replication of the adenovirus genome complexed with viral core proteins; however, isoform 2 specific activity is higher.

关联

项与 SET 相关的药物

OP-449

靶点

SET

作用机制

SET inhibitors

在研机构-

原研机构

Cognosci, Inc.

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SET 相关的临床结果

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100 项与 SET 相关的转化医学

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0 项与 SET 相关的专利（医药）

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862

项与 SET 相关的文献（医药）

2024-02-14·Nature communications

Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis.

Article

作者: Wenbin Xu ; Han Yao ; Zhen Wu ; Xiaojun Yan ; Zishan Jiao ; Yajing Liu ; Meng Zhang ; Donglai Wang

Metastasis is the major cause of lung cancer-related death, but the mechanisms governing lung tumor metastasis remain incompletely elucidated. SE translocation (SET) is overexpressed in lung tumors and correlates with unfavorable prognosis. Here we uncover SET-associated transcription factor, zinc finger and BTB domain-containing protein 11 (ZBTB11), as a prometastatic regulator in lung tumors. SET interacts and collaborates with ZBTB11 to promote lung cancer cell migration and invasion, primarily through SET-ZBTB11 complex-mediated transcriptional activation of matrix metalloproteinase-9 (MMP9). Additionally, by transcriptional repression of proline-rich Gla protein 2 (PRRG2), ZBTB11 links Yes-associated protein 1 (YAP1) activation to drive lung tumor metastasis independently of SET-ZBTB11 complex. Loss of ZBTB11 suppresses distal metastasis in a lung tumor mouse model. Overexpression of ZBTB11 is recapitulated in human metastatic lung tumors and correlates with diminished survival. Our study demonstrates ZBTB11 as a key metastatic regulator and reveals diverse mechanisms by which ZBTB11 modulates lung tumor metastasis.

2024-02-06·International journal of biological macromolecules

Structural analysis of polysaccharide from Inonotus obliquus and investigate combined impact on the sex hormones, intestinal microbiota and metabolism in SPF male mice.

Article

作者: Binhong Hu ; Wenjing Zhou ; Xin Deng ; Mengxue Sun ; Rong Sun ; Qing Li ; Jingyuan Ren ; Wei Jiang ; Yanping Wang ; Songqing Liu ; Jiasui Zhan

The dysregulation of sex hormone levels is associated with metabolic disorders such as obesity. Inonotus obliquus polysaccharide (IOP) exhibits a promising therapeutic effect on conditions like obesity and diabetes, potentially linked to its influence on intestinal microbiota and metabolism. The exact cause and mechanisms that link sex hormones, gut microbiota and metabolism are still unknown. In this research, we examined the molecular weight, monosaccharide composition, and glycosidic bond type of IOP. We found that IOP mostly consists of alpha-structured 6‑carbon glucopyranose, with a predominant (1 → 4) linkage to monosaccharides and a uniform distribution. Following this, we administered two different concentrations of IOP to mice through gavage. The results of the enzyme-linked immunosorbent assay (ELISA) demonstrated a significant increase in testosterone (T) levels in the IOP group as compared to the control group. Additionally, the results of tissue immunofluorescence indicated that increased IOP led to a decrease in adiponectin content and an increase in SET protein expression. The study also revealed changes in the intestinal microbiota and metabolic changes in mice through 16S rRNA data and non-targeted LC-MS data, respectively. The study also found that IOP mainly affects pathways linked to glycerophospholipid metabolism. In addition, it has been observed that there is an increase in the number of beneficial bacteria, such as the Eubacterium coprostanoligenes group and g.Lachnospiraceae NK4A136 group, while the levels of metabolites that are linked to obesity or diabetes, such as 1,5-anhydrosorbitol, are reduced. Furthermore, biomarker screening has revealed that the main microorganism responsible for the differences between the three groups is g.Erysipelatoclostridiaceae. In summary, these findings suggest that IOP exerts its therapeutic effects through a synergistic interplay between sex hormones, gut microbiome composition, and metabolic processes.

2024-01-26·Science advances

PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells.

Article

作者: He Xu ; Di Wu ; Mingming Xiao ; Yubin Lei ; Yalan Lei ; Xianjun Yu ; Si Shi

Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.

项与 SET 相关的新闻（医药）

2024-02-22

·今日头条

【Nature子刊】中国医学科学院北京协和医学院王冬来团队：揭示调节肺癌转移新机制

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：转移是肺癌相关死亡的主要原因，但控制肺肿瘤转移的机制仍未完全阐明。SE 易位（SET）在肺肿瘤中过表达，并与不良预后相关。 2024年2月14日，中国医学科学院北京协和医学院基础医学研究所王冬来课题组在《Nature Communications》上发表题为“Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis”的研究文章，研究证明了 ZBTB11 是一种关键的转移调节因子，并揭示了 ZBTB11 调节肺肿瘤转移的多种机制。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-45585-5 研究背景 01 最新的全球癌症统计数据显示，虽然肺癌发病率已降至第二位，但仍然是癌症死亡的主要原因。肺癌在组织学上可分为小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC），后者可进一步分为腺癌（LUAD）、鳞状细胞癌（LUSC）、大细胞癌等。在所有类型的肺癌中，超过40%是腺癌，转移是恶性肿瘤晚期的标志，是患者肺癌相关死亡的主要原因。然而，肺癌转移的调控机制仍不完全清楚。癌蛋白 SET 最初是在急性未分化白血病（AUL）研究中发现的，在研究染色体易位引起的 DNA 断点时发现了一种新的致癌 SET-CAN 融合基因。条件基因敲除小鼠模型中 SET 表达的完全丧失揭示了胚胎致死表型，证明了 SET 在调节正常发育中的关键作用。更引人注目的是，SET过表达是包括肺癌在内的不同类型癌症中的常见事件，这表明SET在成体细胞中的异常表达有助于肿瘤的发生和/或进展。通过单独或联合策略靶向异常 SET 可能会触发细胞质和细胞核参与的肿瘤机制，包括肺癌，干预。然而，决定 SET 用于肺癌转移调节的细胞核内的主要 TFs 仍然不明确。据报道，ZBTB11 参与了长链非编码 RNA （lncRNA） DUBR 介导的肺癌细胞迁移和侵袭，这表明 ZBTB11 在肺癌进展过程中具有潜在作用。然而， ZBTB11 在肺癌中控制的精确转录谱、调控网络和生物学后果在很大程度上仍然未知。研究进展 02 为了研究肺癌细胞中 SET 和 ZBTB11 之间的功能相互作用，我们试图鉴定 SET 介导的 ZBTB11 直接靶基因的调控。为此，我们首先在SET耗竭96小时后通过RNA-seq评估H1299细胞中的差异表达基因（图3a）。如图 3b 所示，我们鉴定了 164 和 145 个基因，它们在 SET 敲低时分别上调和下调。同样，大多数SET调节的基因也富集在蛋白质编码类别中（~67%，207，图3c）。基于这些数据集，我们发现了 35 个推定的 ZBTB11 直接靶基因，这些基因受 SET（图3d）的共调控。有趣的是，这些基因可以清楚地分为两组：18 个基因在 SET 和 ZBTB11 耗竭时被转录抑制，17 个基因在 SET 和 ZBTB11 耗竭时被转录激活（图3e）。SET/ZBTB11 共调控靶基因的转录谱表明 SET 可能与 ZBTB11 在转录调控方面具有功能协同作用。值得注意的是，GO分析显示，由共调控靶基因富集的顶级生物过程是“细胞外基质组织”，与ZBTB11调控基因富集的生物过程完全相同（图3f）。此外，使用靶标特异性引物的RT-qPCR测定进一步证实，参与细胞外基质组织的MMP9、MMP19、SPARC、PECAM1、SPP1和COL14A1基因确实在H1299细胞中受到SET和ZBTB11的共同调节（图3g）。在 H1975 肺癌细胞中，这些基因在 SET 和/或 ZBTB11 敲低时的类似转录调控也被概括。 SET与ZBTB11在转录调控方面合作总的来说，这些数据表明 SET 与 ZBTB11 在转录调控中合作，并促使我们关注 SET-ZBTB11 蛋白复合物在肿瘤发生和进展时调节细胞外基质相关生物过程的潜在作用。研究结果 03 在这项研究中，我们将 ZBTB11 确定为细胞核中癌蛋白 SET 的结合伙伴。对 ChIP-seq 和 RNA-seq 的综合分析表明，ZBTB11 在肺癌细胞中充当转录因子。SET通过作为辅因子与ZBTB11合作进行转录调控，SET和ZBTB11之间的相互作用在调节肺癌细胞的转移行为中至关重要。从机制上讲，我们发现 MMP9 是有助于 SET-ZBTB11 复合物介导的转移调节的主要下游效应子。此外，ZBTB11 通过转录抑制 PRRG2 表现出一种作用模式，与 YAP1 的激活建立连接，以 SET-ZBTB11 复合物非依赖性方式促进肺肿瘤转移。更重要的是，ZBTB11的条件性敲除可显著抑制体内遗传病变诱导的原发性肺肿瘤的远端转移。综上所述，我们的研究表明，SET结合伙伴ZBTB11在调节肺肿瘤转移中起着关键作用。参考资料： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-45585-5 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

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