Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis.
Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis.
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DOI：
10.1371/journal.pone.0114104
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zúñiga-Ramos J
中科院分区：
文献类型：
--
作者：
Ávila-Moreno F;Armas-López L;Álvarez-Moran AM;López-Bujanda Z;Ortiz-Quintero B;Hidalgo-Miranda A;Urrea-Ramírez F;Rivera-Rosales RM;Vázquez-Manríquez E;Peña-Mirabal E;Morales-Gómez J;Vázquez-Minero JC;Téllez-Becerra JL;Ramírez-Mendoza R;Ávalos-Bracho A;de Alba EG;Vázquez-Santillán K;Maldonado-Lagunas V;Santillán-Doherty P;Piña-Sánchez P;Zúñiga-Ramos J
肺癌是全球恶性疾病死亡的主要原因，其中非小细胞（NSCLC）亚型占大多数病例。非小细胞肺癌（NSCLC）的特征是频繁的基因组失衡和拷贝数变异（CNVs），但与临床预后和治疗失败相关的表观遗传学畸变仍未完全确定。在本研究中，共纳入了55例肺癌患者，我们进行了基因组和基因表达分析，免疫组化蛋白检测，DNA甲基化和染色质免疫沉淀分析，以获得与NSCLC患者预后和化疗反应相关的遗传和表观遗传特征。最后，在NSCLC细胞系A-427和INER-37中评估siRNA转染介导的遗传沉默和顺铂细胞毒性测定，以描述涉及的化学抗性机制。我们的结果在7p22.3-p21.1和7p15.3-p15.2细胞遗传学区域发现了高频率的CNVs（66-51%的病例）。然而，在7p21.2-p21.1位点，尽管没有CNVs，DNA甲基化变化不大，但MEOX 2，HDAC 9，TWIST 1和AhR等基因仍出现过表达。相反，MEOX 2和TWIST 1的启动子序列显示抑制性组蛋白标记H3 K27 me 3显著降低/减少，而活性组蛋白标记H3 K4 me 3水平增加。最后，这些结果以MEOX 2和TWIST 1过表达依赖的方式与NSCLC患者的不良存活率和NSCLC细胞系中对肿瘤药物的细胞耐药性相关。总之，我们首次报道MEOX 2参与化疗耐药，而与高CNV无关，但它显著依赖于H3 K27 me 3富集，可能与NSCLC患者的侵袭性和化疗失败相关，但必须进行额外的临床研究以证实我们的发现作为NSCLC患者新的可能的临床标志物。
Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assessed to describe chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (66–51% of cases) in the 7p22.3–p21.1 and 7p15.3–p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2–p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients.
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影响因子：
5.7
作者：
de Lucio, B;Manuel, V;Barrera-Rodríguez, R
通讯作者：
Barrera-Rodríguez, R
影响因子：
3.7
作者：
Irelan, Jeffrey T.;del Arroyo, Ana Gutierrez;Chanda, Sumit K.
通讯作者：
Chanda, Sumit K.
影响因子：
--
作者：
Kitada, Kunio;Yamasaki, Tomoaki
通讯作者：
Yamasaki, Tomoaki
影响因子：
30.8
作者：
McKay, James D.;Hung, Rayjean J.;Gaborieau, Valerie;Boffetta, Paolo;Chabrier, Amelie;Byrnes, Graham;Zaridze, David;Mukeria, Anush;Szeszenia-Dabrowska, Neonilia;Lissowska, Jolanta;Rudnai, Peter;Fabianova, Eleonora;Mates, Dana;Bencko, Vladimir;Foretova, Lenka;Janout, Vladimir;McLaughlin, John;Shepherd, Frances;Montpetit, Alexandre;Narod, Steven;Krokan, Hans E.;Skorpen, Frank;Elvestad, Maiken Bratt;Vatten, Lars;Njolstad, Inger;Axelsson, Tomas;Chen, Chu;Goodman, Gary;Barnett, Matt;Loomis, Melissa M.;Lubinski, Jan;Matyjasik, Joanna;Lener, Marcin;Oszutowska, Dorota;Field, John;Liloglou, Triantafillos;Xinarianos, George;Cassidy, Adrian;Zelenika, Diana;Boland, Anne;Delepine, Marc;Foglio, Mario;Lechner, Doris;Matsuda, Fumihiko;Blanche, Helene;Gut, Ivo;Heath, Simon;Lathrop, Mark;Brennan, Paul
通讯作者：
Brennan, Paul
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA