Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma
Abstract N6‐methyladenosine (m6A) serves as one of the crucial RNA modifications for genes involved in cancer progression. Here, 7273 expression quantitative trait loci potentially regulating 30 m6A pathway genes are identified from the GTEx database, with 69 single nucleotide polymorphisms signific...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202407652 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540885802287104 |
|---|---|
| author | Lei Cheng Qiangsheng Hu Yanan Wang Wei Nie Haijiao Lu Bo Zhang Genming Zhao Shiyun Ding Feng Pan Yinchen Shen Runbo Zhong Ruoxin Zhang |
| author_facet | Lei Cheng Qiangsheng Hu Yanan Wang Wei Nie Haijiao Lu Bo Zhang Genming Zhao Shiyun Ding Feng Pan Yinchen Shen Runbo Zhong Ruoxin Zhang |
| author_sort | Lei Cheng |
| collection | DOAJ |
| description | Abstract N6‐methyladenosine (m6A) serves as one of the crucial RNA modifications for genes involved in cancer progression. Here, 7273 expression quantitative trait loci potentially regulating 30 m6A pathway genes are identified from the GTEx database, with 69 single nucleotide polymorphisms significantly associated with survival of non‐small cell lung carcinoma (NSCLC) patients (n = 1523) from the ongoing genome‐wide association study after false positive probability tests. Notably, the rs151198415 locus, situated in a potential enhancer region, demonstrated a prolonged survival effect with the C>CCACG insertion, which is validated in an independent prospective cohort (n = 237), yielding a pooled hazard ratio of 0.72 (p = 0.007). Mechanistically, the rs151198415 C>CCACG insertion engaged in long‐range interaction with the promoter of m6A eraser ALKBH5, promoting ALKBH5 transcription by the creation of an EGR1 binding site. Then, ALKBH5 upregulated FBXL5 expression by m6A demethylation, which is dependent on the ALKBH5 H204 amino acid site and specific m6A sites on FBXL5 mRNA. Finally, the ALKBH5‐FBXL5 axis reduces intracellular reactive oxygen species levels, leading to PI3K/AKT and NF‐kB pathway inhibition and consequently suppresses NSCLC proliferation and metastasis in vitro and in vivo. Triggered by an insertion variant, this remote cis‐regulation of m6A eraser and the downstream molecular events modulate the survival of NSCLC patients. |
| format | Article |
| id | doaj-art-2f46111053e44c21afbd4d4627849e2f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2f46111053e44c21afbd4d4627849e2f2025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202407652Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung CarcinomaLei Cheng0Qiangsheng Hu1Yanan Wang2Wei Nie3Haijiao Lu4Bo Zhang5Genming Zhao6Shiyun Ding7Feng Pan8Yinchen Shen9Runbo Zhong10Ruoxin Zhang11Department of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Thoracic Surgery Shanghai Pulmonary Hospital Tongji University School of Medicine Shanghai 200433 ChinaDepartment of Medical Oncology The Affiliated Hospital of Qingdao University Qingdao Shandong 266000 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Epidemiology School of Public Health Key Laboratory of Public Health Safety Ministry of Education Fudan University Shanghai 200032 ChinaDepartment of Epidemiology School of Public Health Key Laboratory of Public Health Safety Ministry of Education Fudan University Shanghai 200032 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Respiratory and Critical Care Medicine Shanghai Chest Hospital Shanghai Jiaotong University School of Medicine Huaihai West Road No.241 Shanghai 200030 ChinaDepartment of Epidemiology School of Public Health Key Laboratory of Public Health Safety Ministry of Education Fudan University Shanghai 200032 ChinaAbstract N6‐methyladenosine (m6A) serves as one of the crucial RNA modifications for genes involved in cancer progression. Here, 7273 expression quantitative trait loci potentially regulating 30 m6A pathway genes are identified from the GTEx database, with 69 single nucleotide polymorphisms significantly associated with survival of non‐small cell lung carcinoma (NSCLC) patients (n = 1523) from the ongoing genome‐wide association study after false positive probability tests. Notably, the rs151198415 locus, situated in a potential enhancer region, demonstrated a prolonged survival effect with the C>CCACG insertion, which is validated in an independent prospective cohort (n = 237), yielding a pooled hazard ratio of 0.72 (p = 0.007). Mechanistically, the rs151198415 C>CCACG insertion engaged in long‐range interaction with the promoter of m6A eraser ALKBH5, promoting ALKBH5 transcription by the creation of an EGR1 binding site. Then, ALKBH5 upregulated FBXL5 expression by m6A demethylation, which is dependent on the ALKBH5 H204 amino acid site and specific m6A sites on FBXL5 mRNA. Finally, the ALKBH5‐FBXL5 axis reduces intracellular reactive oxygen species levels, leading to PI3K/AKT and NF‐kB pathway inhibition and consequently suppresses NSCLC proliferation and metastasis in vitro and in vivo. Triggered by an insertion variant, this remote cis‐regulation of m6A eraser and the downstream molecular events modulate the survival of NSCLC patients.https://doi.org/10.1002/advs.202407652Cis‐regulationgenetic variantsm6A pathwayNSCLCsurvival |
| spellingShingle | Lei Cheng Qiangsheng Hu Yanan Wang Wei Nie Haijiao Lu Bo Zhang Genming Zhao Shiyun Ding Feng Pan Yinchen Shen Runbo Zhong Ruoxin Zhang Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma Advanced Science Cis‐regulation genetic variants m6A pathway NSCLC survival |
| title | Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma |
| title_full | Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma |
| title_fullStr | Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma |
| title_full_unstemmed | Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma |
| title_short | Cis‐Regulation of an m6A Eraser by an Insertion Variant Associated with Survival of Patients With Non‐Small Cell Lung Carcinoma |
| title_sort | cis regulation of an m6a eraser by an insertion variant associated with survival of patients with non small cell lung carcinoma |
| topic | Cis‐regulation genetic variants m6A pathway NSCLC survival |
| url | https://doi.org/10.1002/advs.202407652 |
| work_keys_str_mv | AT leicheng cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT qiangshenghu cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT yananwang cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT weinie cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT haijiaolu cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT bozhang cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT genmingzhao cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT shiyunding cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT fengpan cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT yinchenshen cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT runbozhong cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma AT ruoxinzhang cisregulationofanm6aeraserbyaninsertionvariantassociatedwithsurvivalofpatientswithnonsmallcelllungcarcinoma |