Super enhancer associated RAI14 is a new potential biomarker in lung adenocarcinoma.

Chongze Yuan,Yihua Sun,Yawei Zhang,Muyu Kuang,Zongwei Chen,Xiaoting Tao,Hong Hu,Haiquan Chen,Shengjian Fang

doi:10.18632/oncotarget.22165

Abstract

PurposeTyrosine kinase inhibitors (TKIs) are widely used to treat lung adenocarcinoma patients with EGFR mutations or ALK-fusions. However, patients with wild-type genes or TKIs-resistant mutations lack effective therapeutic targets. Extensive studies reveal that super enhancer (SE), a large cis-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.Experimental DesignChromatin 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.ResultsSE associated with many new oncogenes in lung adenocarcinoma, among which, RAI14 was up-regulated in A549 and 31 of 71 patients. High expression of RAI14 could inhibit cell proliferation, indicating its potential as a new biomarker for lung adenocarcinoma.

Highlights

One of the most malignant tumors yet discovered, lung cancer has been the leading cause of mortality of male worldwide
super enhancer (SE) associated with many new oncogenes in lung adenocarcinoma, among which, RAI14 was up-regulated in A549 and 31 of 71 patients
In GO analysis, compared with normal human lung fibroblasts (NHLF), more tumor-related biological processes were enriched in 3 lung adenocarcinoma cell lines, including cell proliferation, migration and differentiation (Figure 2A)

Summary

Introduction

One of the most malignant tumors yet discovered, lung cancer has been the leading cause of mortality of male worldwide. Numerous genomic alterations have been found in correlation with oncogenesis and cancer progress, such as EGFR mutations, ALK-fusions, and KRAS mutations. Patients with EGFR mutations or ALK-fusions are recommended to receive targeted therapy of tyrosine kinase inhibitors www.impactjournals.com/oncotarget (TKIs), which significantly prevents the progression of cancer and improves patients’ prognosis [6]. MEK inhibitors have been approved for the treatment of KRAS mutations positive colorectal cancer patients, but they did not show priority to docetaxel in patients with previously treated KRAS mutations positive NSCLC [12]

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Conclusion