Abstract
Histone H2AX is a tumor suppressor protein that plays an important role in apoptosis. However, the mechanism underlying the association of H2AX with apoptosis in cancer cells remains elusive. Here, we showed that H2AX knockdown in lung cancer A549 cells affected the expression of 16 microRNAs (miRNAs), resulting in the downregulation of 1 and the upregulation of 15 miRNAs. MicroRNA-3196 (miR-3196) was identified as a target of H2AX and shown to inhibit apoptosis in lung cancer cells by targeting p53 upregulated modulator of apoptosis (PUMA). Phosphorylated H2AX (γH2AX) was shown to bind to the promoter of miR-3196 and regulate its expression. In addition, H2AX phosphorylation increased H3K27 trimethylation in the promoter region of miR-3196 and inhibited the binding of RNA polymerase II to the promoter of miR-3196, leading to the inhibition of miR-3196 transcription. Taken together, these results indicated that H2AX phosphorylation regulates apoptosis in lung cancer cells via the miR-3196/PUMA pathway.
Highlights
Lung cancer, known as lung carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in the tissues of the lung
We revealed that VP16 induced H2AX phosphorylation at Ser139; we confirmed in detail whether miR-3196 expression was really regulated by H2AX phosphorylation
Www.impactjournals.com/oncotarget induced apoptosis by downregulating p53 upregulated modulator of apoptosis (PUMA) (Figure 4), we investigated whether miR-3196 expression is directly regulated by H2AX. miR-3196 is an intergenic miRNA located in the BIRC7 gene and its promoter is unknown; we cloned the promoter of the BIRC7 gene [12] into the pGL3-enhancer vector carrying the luciferase reporter gene (Figure 5A, left panel)
Summary
Known as lung carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in the tissues of the lung. The main primary types of lung cancer are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). NSCLC is the most common form of lung cancer and includes adenocarcinomas, squamous cell carcinomas, and large cell carcinomas. Lung cancer, which is the most common malignancy and the leading cause of cancer-related death, was responsible for 610,000 deaths in 2015 in China [1]. In contrast to the steady increase in survival rates for most cancers, the 5-year relative survival rate for lung cancer remains low [2]. The identification of new candidate molecules involved in lung cancer is important to improve the diagnosis, prevention, and treatment of this disease
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