NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC).
NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC).
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DOI：
10.1016/j.fob.2013.12.003
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发表时间：
2014
期刊：
影响因子：
2.6
通讯作者：
Castilho RM
中科院分区：
文献类型：
--
作者：
Almeida LO;Abrahao AC;Rosselli-Murai LK;Giudice FS;Zagni C;Leopoldino AM;Squarize CH;Castilho RM
以顺铂为基础的化疗是头颈部鳞状细胞癌（HNSCC）的标准治疗选择。铂类药物治疗的有效性直接受到肿瘤耐药性发展的影响。多种信号通路与肿瘤耐药性有关，包括核因子κ B（NFκB）的激活。我们探索了NFκB通过组蛋白修饰驱动HNSCC耐药的新机制。组蛋白的翻译后修饰改变染色质结构，促进介导DNA修复、转录和其他过程的核因子的结合。我们发现，具有活性NFκB信号传导的耐药HNSCC细胞通过降低核BRCA 1水平和促进组蛋白脱乙酰化（染色质致密化）对化疗作出反应。这种分子特征的激活导致DNA损伤修复受损，组蛋白γH2AX的积累延长和基因组不稳定性增加。我们发现，使用HDAC抑制剂药理学诱导组蛋白乙酰化可预防NFκ B诱导的顺铂耐药。此外，在HNSCC中沉默NFκB诱导肿瘤组蛋白的乙酰化，导致顺铂治疗后化疗耐药性降低和细胞毒性增加。总的来说，这些发现表明，由NFκ B诱导的组蛋白修饰引起的HNSCC的表观遗传修饰构成了HNSCC化学抗性的新分子机制。因此，靶向抑制HDAC可作为一种可行的治疗策略，用于破坏NFκB引起的肿瘤耐药性。化疗耐药的HNSCC细胞具有组蛋白的脱乙酰化和活性NFκB信号传导。组蛋白去乙酰化降低BRCA1水平并增强基因组不稳定性。组蛋白脱乙酰酶（HDAC）抑制剂使HNSCC对化疗敏感。NFκB信号通过诱导组蛋白去乙酰化驱动HNSCC化学抗性。NFκB抑制导致组蛋白乙酰化，并使HNSCC对化疗敏感。
Cisplatin-based chemotherapy is the standard treatment of choice for head and neck squamous cell carcinoma (HNSCC). The efficiency of platinum-based therapies is directly influenced by the development of tumor resistance. Multiple signaling pathways have been linked to tumor resistance, including activation of nuclear factor kappa B (NFκB). We explore a novel mechanism by which NFκB drives HNSCC resistance through histone modifications. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. We found that chemoresistant HNSCC cells with active NFκB signaling respond to chemotherapy by reducing nuclear BRCA1 levels and by promoting histone deacetylation (chromatin compaction). Activation of this molecular signature resulted in impaired DNA damage repair, prolonged accumulation of histone γH2AX and increased genomic instability. We found that pharmacological induction of histone acetylation using HDAC inhibitors prevented NFκB-induced cisplatin resistance. Furthermore, silencing NFκB in HNSCC induced acetylation of tumor histones, resulting in reduced chemoresistance and increased cytotoxicity following cisplatin treatment. Collectively, these findings suggest that epigenetic modifications of HNSCC resulting from NFκB-induced histone modifications constitute a novel molecular mechanism responsible for chemoresistance in HNSCC. Therefore, targeted inhibition of HDAC may be used as a viable therapeutic strategy for disrupting tumor resistance caused by NFκB. Chemoresistant HNSCC cells have deacetylation of histones and active NFκB signaling. Histone deacetylation reduces BRCA1 levels and enhances genomic instability. Histone deacetylase (HDAC) inhibitors sensitize HNSCC to chemotherapy. NFκB signaling drives HNSCC chemoresistance by inducing histone deacetylation. NFκB inhibition results in histone acetylation and sensitizes HNSCC to chemotherapy.
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DOI：
10.1002/hed.10274
发表时间：
2003-08-01
影响因子：
2.9
作者：
Bradford, CR;Zhu, SB;Carey, TE
通讯作者：
Carey, TE
影响因子：
56.9
作者：
Delhase, M;Hayakawa, M;Karin, M
通讯作者：
Karin, M
影响因子：
14.9
作者：
Deng CX
通讯作者：
Deng CX
DOI：
10.1073/pnas.0508825103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Basile, John R.;Castilho, Rogerio M.;Gutkind, J. Silvio
通讯作者：
Gutkind, J. Silvio
影响因子：
64.5
作者：
Jacobs, MD;Harrison, SC
通讯作者：
Harrison, SC