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Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p 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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251189/ https://www.ncbi.nlm.nih.gov/pubmed/35795202 http://dx.doi.org/10.3389/fgene.2022.805960 |
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author | Yang, Qin Zhu, Lin Ye, Mao Zhang, Bin Zhan, Peihe Li, Hui Zou, Wen Liu, Jing |
author_facet | Yang, Qin Zhu, Lin Ye, Mao Zhang, Bin Zhan, Peihe Li, Hui Zou, Wen Liu, Jing |
author_sort | Yang, Qin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9251189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92511892022-07-05 Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC Yang, Qin Zhu, Lin Ye, Mao Zhang, Bin Zhan, Peihe Li, Hui Zou, Wen Liu, Jing Front Genet Genetics 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. Frontiers Media S.A. 2022-06-20 /pmc/articles/PMC9251189/ /pubmed/35795202 http://dx.doi.org/10.3389/fgene.2022.805960 Text en Copyright © 2022 Yang, Zhu, Ye, Zhang, Zhan, Li, Zou and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Yang, Qin Zhu, Lin Ye, Mao Zhang, Bin Zhan, Peihe Li, Hui Zou, Wen Liu, Jing Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title | Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title_full | Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title_fullStr | Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title_full_unstemmed | Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title_short | Tumor Suppressor 4.1N/EPB41L1 is Epigenetic Silenced by Promoter Methylation and MiR-454-3p in NSCLC |
title_sort | tumor suppressor 4.1n/epb41l1 is epigenetic silenced by promoter methylation and mir-454-3p in nsclc |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251189/ https://www.ncbi.nlm.nih.gov/pubmed/35795202 http://dx.doi.org/10.3389/fgene.2022.805960 |
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