Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer.
Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer.
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阿司匹林与p300协同激活H3K9的乙酰化，促进FasL介导的结直肠癌干细胞样细胞凋亡。
DOI：
10.7150/thno.24284
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Chen Z;Li W;Qiu F;Huang Q;Jiang Z;Ye J;Cheng P;Low C;Guo Y;Yi X;Chen W;Yu Y;Han Y;Wu J;Jin S;Kong D;Huang J
肿瘤干细胞样细胞（Cancer stem-like cells，CSCs）被认为是大肠癌（colorectal cancer，CRC）生长和复发的关键驱动力，是肿瘤治疗的重要靶点。流行病学证据表明，每日使用阿司匹林可降低CRC的总体死亡率和远处转移的风险。我们研究了阿司匹林对CRC中CSC的作用及其机制。方法：在细胞模型和患者样本中分析阿司匹林治疗后CSC的比例。采用化学修饰法和免疫沉淀法检测阿司匹林的靶蛋白。构建了基于CRISPR技术的基因座特异性光诱导表观遗传修饰系统，以验证这些分子事件中的因果关系。在异种移植模型中进行体内表征。结果如下：我们发现阿司匹林诱导富集的结直肠CSC中的细胞凋亡，抑制肿瘤进展，并增强化疗剂的抗肿瘤作用。此外，阿司匹林直接与细胞核中的p300相互作用，促进H3 K9乙酰化，激活FasL表达，并诱导结直肠CSC的凋亡。值得注意的是，阿司匹林的这些作用在非CSC中不存在，因为H3 K9在非CSC中是高甲基化的，并且该作用不由其他NSAID诱导。此外，阿司匹林可以抑制富含奥沙利铂的CSC，并作为辅助治疗。结论：综上所述，我们揭示了一种独特的表观遗传和Cox非依赖性途径（p300-AcH 3 K9-FasL轴），阿司匹林通过该途径消除结直肠CSC。这些发现为阿司匹林的治疗意义建立了一个创新框架。
Cancer stem-like cells (CSCs) have been proposed as a key driving force of tumor growth and relapse in colorectal cancer (CRC), and therefore, they are promising targets for cancer therapy. Epidemiological evidence has suggested that the daily use of aspirin reduces overall mortality of CRC and the risk of distant metastasis. We investigated the effect and mechanism of aspirin on CSCs in CRC. Methods: The ratio of CSCs was analyzed after aspirin treatment both in a cell model and patient samples. Chemically modified aspirin and immunoprecipitation were adopted to detect the target proteins of aspirin. A locus-specific light-inducible epigenetic modification system based on CRISPR technology was constructed to verify the causal relationship in these molecular events. In vivo characterization was performed in a xenograft model. Results: We found that aspirin induces apoptosis in enriched colorectal CSCs, inhibits tumor progression, and enhances the anti-neoplastic effects of chemotherapeutic agents. Furthermore, aspirin directly interacts with p300 in the nucleus, promotes H3K9 acetylation, activates FasL expression, and induces apoptosis in colorectal CSCs. Notably, these effects of aspirin are absent in non-CSCs since H3K9 is hypermethylated in non-CSCs and the effects are not induced by other NSAIDs. In addition, aspirin can suppress oxaliplatin-enriched CSCs and serve as an adjuvant therapy. Conclusions: Taken together, we revealed a unique epigenetic and cox-independent pathway (p300-AcH3K9-FasL axis) by which aspirin eliminates colorectal CSCs. These findings establish an innovative framework of the therapeutic significance of aspirin.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
16.6
作者：
Li J;Yu B;Deng P;Cheng Y;Yu Y;Kevork K;Ramadoss S;Ding X;Li X;Wang CY
通讯作者：
Wang CY
影响因子：
16.6
作者：
Ceppi, Paolo;Hadji, Abbas;Kohlhapp, Frederick J.;Pattanayak, Abhinandan;Hau, Annika;Liu, Xia;Liu, Huiping;Murmann, Andrea E.;Peter, Marcus E.
通讯作者：
Peter, Marcus E.
DOI：
10.1073/pnas.0506893102
发表时间：
2005-11-22
影响因子：
11.1
作者：
Gao, JJ;Liu, XP;Rigas, B
通讯作者：
Rigas, B