RBM14 as a novel epigenetic-activated tumor oncogene is implicated in the reprogramming of glycolysis in lung cancer.

BACKGROUND: RNA-binding motif protein 14 (RBM14) is upregulated in a variety of tumors. However, the expression and biological role of RBM14 in lung cancer remain unclear. METHODS: Chromatin immunoprecipitation and PCR were carried out to measure the levels of sedimentary YY1, EP300, H3K9ac, and H3K27ac in the RBM14 promoter. Co-immunoprecipitation was used to verify the interaction between YY1 and EP300. Glycolysis was investigated according to glucose consumption, lactate production, and the extracellular acidification rate (ECAR). RESULTS: RBM14 level is increased in lung adenocarcinoma (LUAD) cells. The increased RBM14 expression was correlated with TP53 mutation and individual cancer stages. A high level of RBM14 predicted a poorer overall survival of LUAD patients. The upregulated RBM14 in LUAD is induced by DNA methylation and histone acetylation. The transcription factor YY1 directly binds to EP300 and recruits EP300 to the promoter regions of RBM14, which further enhances H3K27 acetylation and promotes RBM14 expression. YY1-induced upregulation of RBM14 promoted cell growth and inhibited apoptosis by affecting the reprogramming of glycolysis. CONCLUSIONS: These results indicated that epigenetically activated RBM14 regulated growth and apoptosis by regulating the reprogramming of glycolysis and RBM14 may serve as a promising biomarker and therapeutic target for LUAD.

The transcription factor TEAD4 enhances lung adenocarcinoma progression through enhancing PKM2 mediated glycolysis.

Lung adenocarcinoma (LUAD) is a deadly disease with a hallmark of aberrant metabolism. TEA domain 4 (TEAD4) is involved in the progression of several forms of cancer including LUAD. However, the role of TEAD4 in LUAD glucose metabolism is rarely reported as well as its potential mechanisms. Pyruvate kinase isozymes M2 (PKM2), the key regulatory enzymes in glycolysis, was predicted to be a target for TEAD4 by bioinformatics analysis. Thus, we aimed to explore whether TEAD4/PKM2 axis was related to LUAD glucose metabolism and malignant phenotype. The expression level of TEAD4 and PKM2 was measured by quantitative real-time PCR and Western blot. Luciferase reporter assay were employed to verify the effect of TEAD4 on PKM2 promoter as well as TEAD4/PKM2 axis on reporter activity of hypoxia inducible factor-1α (HIF-1α). Glycolysis was investigated according to glucose consumption, lactate production and the extracellular acidification rate. The present study indicated that TEAD4 and PKM2 were upregulated in LUAD and closely related to prognosis. Mechanistic investigations identified that TEAD4 played a key role as a transcription factor and promoted PKM2 transcription and expression, which further altered the reporter activity of HIF-1α and upregulated HIF-1α-targeted glycolytic genes glucose transporter-1 and hexokinase II. Functional assays revealed that TEAD4 and PKM2 affected glycolytic and 2-DG blocked the positive function of TEAD4 and PKM2 on glycolytic. Besides, TEAD4/PKM2 axis affects LUAD cell viability, apoptosis, migration, and invasion. Together, these data provided evidence that both TEAD4 and PKM2 were poor prognosticator. Targeting TEAD4/PKM2 axis might be an effective therapeutic strategy for LUAD.

H3K27 acetylation activated-CCS regulates autophagy and apoptosis of lung cancer by alleviating oxidative stress.

Copper chaperone for superoxide dismutase (CCS) is abnormally expressed in various human malignancies. However, the function and mechanism of CCS in lung cancer progression remain unclear. In the current study, CCS protein and mRNA levels were found to be increased in lung adenocarcinoma (LUAD) tissue and cell lines. Patients with higher CCS levels had a poorer prognosis. Decreasing the enrichment of histone H3 Lys27 acetylation (H3K27ac) by A-485 inhibited CCS expression. CCS depletion upregulated reactive oxygen species (ROS) levels, aggravated oxidative stress, inhibited autophagy, inhibited cell survival, and promoted apoptosis. The treatment of antioxidant N-Acetyl-L-cysteine (NAC) rescued these changes induced by CCS depletion. CCS also was found to be related to the immune infiltration of CD8 + T cells and regulatory T cells in LUAD. These data indicated that overexpression of CCS activated by H3K27 acetylation relieved oxidative stress, promoted autophagy, and inhibited apoptosis. CCS may be regarded as a potential therapeutic target for LUAD.

Histone demethylase PHF8 promotes cell growth and metastasis of non-small-cell lung cancer through activating Wnt/ß-catenin signaling pathway.

PHD finger protein 8 (PHF8), serving as a histone demethylase, is upregulated in some types of malignant tumors. The role of PHF8 in non-small-cancer lung carcinoma (NSCLC) remains unclear. This study aims to verify the effect of PHF8 in NSCLC and its molecular mechanism. We collected 20 cases of fresh NSCLC and adjacent lung tissues to assess differential expressions of PHF8 by reverse transcription-quantitative PCR (RT-qPCR). Western blot was employed to examine protein levels of PHF8, Wnt1, ß-catenin and epithelial-mesenchymal transition (EMT) related proteins. Chromatin immunoprecipitation assays were executed to confirm the regulatory mechanism of PHF8 and Wnt1. Cell Counting Kit-8 assays and Transwell assays were utilized to identify the effects of PHF8/Wnt1 pathway on cell proliferation, migration and invasion. PHF8 was overexpressed in NSCLC tissues and cells and higher PHF8 expression was correlated with poorer overall survival in NSCLC patients. PHF8 overexpression promoted NSCLC cell proliferation, migration and invasion, while PHF8 knockdown exerted the opposite effect. Mechanistic investigations identified that PHF8 occupied the Wnt1 promoter, leading to a decrease of repressive histone markers H3K9me1, H3K9me2, H3K27me2 and H4K20me1 in the promoter region of the Wnt1 gene, which further promoted the transcription of the Wnt1 gene. PHF8 activated Wnt/ß-catenin signaling pathway through promoting Wnt1 expression. Besides, PHF8 altered the EMT of NSCLC through regulating Wnt1 levels. PHF8, acting as an oncogene and prognostic biomarker in NSCLC, stimulated NSCLC to proliferate, metastasis and EMT by activating Wnt/ß-catenin signaling.