Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma

Abstract

In this study, we aimed to identify novel drivers that would be epigenetically altered through aberrant methylation in early-stage lung adenocarcinoma (LADC), regardless of the presence or absence of tobacco smoking-induced epigenetic field defects. Through genome-wide screening for aberrantly methylated CpG islands (CGIs) in 12 clinically uniform, stage-I LADC cases affecting six non-smokers and six smokers, we identified candidate tumor-suppressor genes (TSGs) inactivated by hypermethylation. Through systematic expression analyses of those candidates in panels of additional tumor samples and cell lines treated or not treated with 5-aza-deoxycitidine followed by validation analyses of cancer-specific silencing by CGI hypermethylation using a public database, we identified TRIM58 as the most prominent candidate for TSG. TRIM58 was robustly silenced by hypermethylation even in early-stage primary LADC, and the restoration of TRIM58 expression in LADC cell lines inhibited cell growth in vitro and in vivo in anchorage-dependent and -independent manners. Our findings suggest that aberrant inactivation of TRIM58 consequent to CGI hypermethylation might stimulate the early carcinogenesis of LADC regardless of smoking status; furthermore, TRIM58 methylation might be a possible early diagnostic and epigenetic therapeutic target in LADC.

The Association and Clinical Significance of CDKN2A Promoter Methylation in Head and Neck Squamous Cell Carcinoma: a Meta-Analysis

“…We further assessed the diagnostic effect of CDKN2A promoter methylation in HNSCC precancerous patients vs. healthy subjects. Interestingly, the AUC was 0.95 and revealed efficient diagnostic power of CDKN2A promoter methylation in diagnosis of HNSCCs from precancerous samples, which can reveal that methylation is a relatively early molecular change during carcinogenesis as previous study concluded [13,104]. Some studies have suggested that DNA methylation can be detected in body fluid samples (blood, bronchial aspirates, brushing, saliva, and urine) as a noninvasive molecular biomarker for cancer screening and diagnosis [105][106][107].…”

Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer

“…Notably, OR5T1 protein is predicted to be N-glycosylated at Asn17, suggesting the possibility that LRRC26 downregulation may be important for ORT51 glycosylation. To further identify significantly overrepresented Gene Ontology terms affected by LRRC26 expression in HCC70 cells, these upregulated or downregulated genes were analyzed using the DAVID algorithm (27,31). The most prominent cluster (annotation cluster 1; gene enrichment score, 3.12) was identified, which contained features related to 'glycoprotein', 'signal peptide', 'secreted' and 'N-linked glycoprotein (GlcNAc)' (Table VI).…”

Predicting Methylation from Sequence and Gene Expression Using Deep Learning with Attention

“…DNA methylation plays a key role in disease development. Specifically, hypermethylation can lead to stable silencing of tumor suppressor genes [21]. This process has therefore been extensively observed and studied in the context of cancer [24], [15], [41], [29].…”