DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer

Abstract

Background Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 ( TREX2 ) locus in laryngeal ( n = 256) and colorectal cancer cases ( n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). Results Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts ( p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 ( p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients ( p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. Conclusions The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies. Electronic supplementary material The online version of this article (10.1186/s13148-019-0666-5) contains supplementary material, which is available to authorized users.

Discovery and validation of the prognostic value of the lncRNAs encoding snoRNAs in patients with clear cell renal cell carcinoma

“…In addition, it is well known that abnormal DNA methylation includes global hypomethylation and regional hypermethylation, in which regional hypermethylation is usually associated with gene silencing. For example, hypermethylation of the CpG shore of the Shh gene resulted in Shh loss, and inhibition of DNA methylation increased Shh expression to halt the initiation of bladder cancer at the early stage of progression [48]; DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) was linked to decreased TREX2 gene expression and protein expression, which may affect drug-induced DNA damage repair in laryngeal cancer [49]; and Epigenetic Silencing of miRNA-338-5p and miRNA-421 drived SPINK1-Positive Prostate Cancer [50]. Besides, a recent study reported that downregulation of CLDN7 due to promoter hypermethylation contributed to human ccRCC progression and poor prognosis [51], indicating DNA methylation may also play vital roles in ccRCC.…”

Development and validation of epigenetic signature predict survival for patients with laryngeal squamous cell carcinoma

“…Joint survival analysis, that is, the methylation and gene expression matched evaluation, was additionally conducted to exploit the prognostic value of MAGEB2, SUSD1, ZNF382, ZNF418 and [13] concluded that a regulatory role of TREX2 DNA methylation for gene expression which might be an To our knowledge, this is the first study carried out a genome-wide integrated analysis of methylation and the transcriptome from TCGA database to seek novel biomarker as potential molecular targeted therapy and to create an epigenetic signature for LSCC patients to optimize therapeutic strategies.…”

“…An increasing number of researches recognize that epigenetic changes such as the hypermethylation of tumor suppressor genes and hypomethylation of oncogenes in the diagnosis, progression and prognosis of LSCC played a critical role[11][12][13]. By quantitative methylation-specific polymerase (qMSP) chain reaction assays in 96 LSCC patients, Shen et al[11] revealed that LZTS2 promoter hypermethylation is linked to risk, progression, and prognosis of LSCC,which can serve as a diagnostic and prognostic biomarker for LSCC.…”

Molecular Subtypes Based on DNA Methylation Profiles can Predict the Prognosis of Patients with Laryngeal Cancer

“…Lili reported that the occurrence of aberrant methylation events in the LINC00886 TSS may accelerate the malignant progression of laryngeal carcinoma [27]. Another study showed that the regulation of gene expression by TREX2 DNA methylation may affect the incidence and survival of laryngeal cancer [21]. Elevated CMCC3 methylation level is a risk factor for male LSCC patients, especially in patients over 55 years of age who have smoking behavior [28].…”