Journal
FRONTIERS IN GENETICS
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2022.805960
Keywords
4; 1N; EPB41L1; lung adenocarcinoma (LUAD); methylation; miR-454-3P; non-small-cell lung cancer (NSCLC); lung squamous cell carcinoma (LUSC)
Categories
Funding
- National Natural Science Foundation of China [81770107, 82003286]
- Natural Science Foundation of Hunan Province [2020JJ4560]
- Scientific Research Foundation of Hunan Provincial Education Department [20B528]
- Guidance Science and Technology Program of Shaoyang City [2019ZD07]
- Fellowship of China Postdoctoral Science Foundation [2020M672474, 2021T140195]
- Changsha Municipal Natural Science Foundation [kq20140421]
- Postgraduate Innovation and Research Project of Central South University [2021zzts0569]
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This study identified the epigenetic mechanisms underlying the reduction of 4.1N/EPB41L1 in NSCLC. The promoter region of the 4.1N/EPB41L1 gene was highly methylated in LUAD and LUSC patients. Higher methylation levels in the 4.1N/EPB41L1 gene promoter were associated with shorter overall survival in LUAD patients and longer overall survival in LUSC patients. The study also found that the expression of miR-454-3p was abnormally high in NSCLC and directly targeted the 4.1N/EPB41L1 mRNA. The findings suggest that promoter hypermethylation and abnormal miR-454-3p expression restrict the expression of 4.1N/EPB41L1 in NSCLC.
Non-small-cell lung cancer (NSCLC) is divided into three major histological types, namely, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large-cell lung carcinoma (LCLC). We previously identified that 4.1N/EPB41L1 acts as a tumor suppressor and is reduced in NSCLC patients. In the current study, we explored the underlying epigenetic mechanisms of 4.1N/EPB41L1 reduction in NSCLC. The 4.1N/EPB41L1 gene promoter region was highly methylated in LUAD and LUSC patients. LUAD patients with higher methylation level in the 4.1N/EPB41L1 gene promoter (TSS1500, cg13399773 or TSS200, cg20993403) had a shorter overall survival time (Log-rank p = 0.02 HR = 1.509 or Log-rank p = 0.016 HR = 1.509), whereas LUSC patients with higher methylation level in the 4.1N/EPB41L1 gene promoter (TSS1500 cg13399773, TSS1500 cg07030373 or TSS200 cg20993403) had a longer overall survival time (Log-rank p = 0.045 HR = 0.5709, Log-rank p = 0.018 HR = 0.68 or Log-rank p = 0.014 HR = 0.639, respectively). High methylation of the 4.1N/EPB41L1 gene promoter appeared to be a relatively early event in LUAD and LUSC. DNA methyltransferase inhibitor 5-Aza-2 '-deoxycytidine restored the 4.1N/EPB41L1 expression at both the mRNA and protein levels. MiR-454-3p was abnormally highly expressed in NSCLC and directly targeted 4.1N/EPB41L1 mRNA. MiR-454-3p expression was significantly correlated with 4.1N/EPB41L1 expression in NSCLC patients (r = -0.63, p < 0.0001). Therefore, we concluded that promoter hypermethylation of the 4.1N/EPB41L1 gene and abnormally high expressed miR-454-3p work at different regulation levels but in concert to restrict 4.1N/EPB41L1 expression in NSCLC. Taken together, this work contributes to elucidate the underlying epigenetic disruptions of 4.1N/EPB41L1 deficiency in NSCLC.
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