Yuan Chongze, Hu Hong, Kuang Muyu, Chen Zongwei, Tao Xiaoting, Fang Shengjian, Sun Yihua, Zhang Yawei, Chen Haiquan
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Oncotarget. 2017 Oct 27;8(62):105251-105261. doi: 10.18632/oncotarget.22165. eCollection 2017 Dec 1.
Tyrosine kinase inhibitors (TKIs) are widely used to treat lung adenocarcinoma patients with mutations or -fusions. However, patients with wild-type genes or TKIs-resistant mutations lack effective therapeutic targets. Extensive studies reveal that super enhancer (SE), a large -regulatory element, is associated with key oncogenes in a variety of cancers. By comparing the effect of SE on lung adenocarcinoma cell lines with normal cell line, this work attempts to find new biomarkers and potential therapeutic targets for lung adenocarcinoma.
Chromatin Immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) of H3K27ac (acetylation on lysine 27 of histone 3) was performed in lung adenocarcinoma cell lines SPC-A1 and SCH-1153. The differences in SE distribution were then analyzed among SPC-A1, SCH-1153, A549 and normal human lung fibroblasts (NHLF) to identify SE-associated oncogenes. The expression of SE-associated oncogenes was then detected by RNA-seq and further verified in 71 patients by real-time PCR.
SE associated with many new oncogenes in lung adenocarcinoma, among which, was up-regulated in A549 and 31 of 71 patients. High expression of could inhibit cell proliferation, indicating its potential as a new biomarker for lung adenocarcinoma.
酪氨酸激酶抑制剂（TKIs）被广泛用于治疗具有突变或融合的肺腺癌患者。然而，具有野生型基因或TKIs耐药突变的患者缺乏有效的治疗靶点。大量研究表明，超级增强子（SE）作为一种大型调控元件，与多种癌症中的关键癌基因相关。通过比较SE对肺腺癌细胞系和正常细胞系的影响，本研究试图寻找肺腺癌的新生物标志物和潜在治疗靶点。
在肺腺癌细胞系SPC-A1和SCH-1153中进行染色质免疫沉淀（ChIP），随后对组蛋白3赖氨酸27乙酰化（H3K27ac）进行高通量DNA测序（ChIP-seq）。然后分析SPC-A1、SCH-1153、A549和正常人肺成纤维细胞（NHLF）之间SE分布的差异，以鉴定与SE相关的癌基因。然后通过RNA-seq检测与SE相关的癌基因的表达，并通过实时PCR在71例患者中进一步验证。
SE与肺腺癌中的许多新癌基因相关，其中，在A549和71例患者中的31例中上调。的高表达可抑制细胞增殖，表明其作为肺腺癌新生物标志物的潜力。
