Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer
Emerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-05-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.868830/full |
| _version_ | 1828282918094503936 |
|---|---|
| author | Cheng Yuan Cheng Yuan Junchang Zhang Junchang Zhang Cuncan Deng Cuncan Deng Yujian Xia Bo Li Bo Li Sijun Meng Sijun Meng Xinghan Jin Xinghan Jin Lvjia Cheng Huafu Li Changhua Zhang Changhua Zhang Changhua Zhang Yulong He Yulong He Yulong He Yulong He |
| author_facet | Cheng Yuan Cheng Yuan Junchang Zhang Junchang Zhang Cuncan Deng Cuncan Deng Yujian Xia Bo Li Bo Li Sijun Meng Sijun Meng Xinghan Jin Xinghan Jin Lvjia Cheng Huafu Li Changhua Zhang Changhua Zhang Changhua Zhang Yulong He Yulong He Yulong He Yulong He |
| author_sort | Cheng Yuan |
| collection | DOAJ |
| description | Emerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human gastric cell lines, we systematically characterized the crosstalk of four epigenetic modification types including H3K4me1, H3K4me3, H3K27ac, and N6-methyladenosine (m6A) and identified a recurrent subtype with high FTO expression and low HDAC1 expression across three independent gastric cancer (GC) cohorts, which we named the epigenetic-modification-dysregulated (EMD) subtype. Patients of the EMD subtype were featured with poor survival, stromal activation, and immune suppression. Extensive relevance to clinical characteristics was observed in the EMD subtype, including the Lauren classification, MSI status, histological grade, TNM stage, the Asian Cancer Research Group classification, and the immune/fibrotic classification. An EMD score was then constructed using WGCNA and ssGSEA algorithms, to precisely recognize the EMD subtype and indicate prognosis and response to immunotherapy in multiple independent GC cohorts. Correlations of the EMD score with tumor mutation burden, tumor purity, aneuploidy score, tumorigenic pathways, TME characteristics, and FTO/HDAC1 ratio were measured. In vitro experiments were performed to demonstrate the correlation between FTO and the epithelial–mesenchymal transition pathway, which suggested FTO as a targetable vulnerability for GC patients with a high EMD score. Altogether, by comprehensively analyzing the epigenetic modification patterns of 1518 GC patients, we identified a novel stromal-activated subtype with poor survival and resistance to immunotherapy, which might benefit from the combined immune checkpoint inhibition therapy with FTO inhibition. |
| first_indexed | 2024-04-13T08:37:37Z |
| format | Article |
| id | doaj.art-451519a5a9e4446088ae224393884049 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T08:37:37Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-451519a5a9e4446088ae2243938840492022-12-22T02:54:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.868830868830Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric CancerCheng Yuan0Cheng Yuan1Junchang Zhang2Junchang Zhang3Cuncan Deng4Cuncan Deng5Yujian Xia6Bo Li7Bo Li8Sijun Meng9Sijun Meng10Xinghan Jin11Xinghan Jin12Lvjia Cheng13Huafu Li14Changhua Zhang15Changhua Zhang16Changhua Zhang17Yulong He18Yulong He19Yulong He20Yulong He21Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDepartment of Thyroid Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaGastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, ChinaThe Institute of Cancer Research, London, United KingdomDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDigestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaGuangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaEmerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human gastric cell lines, we systematically characterized the crosstalk of four epigenetic modification types including H3K4me1, H3K4me3, H3K27ac, and N6-methyladenosine (m6A) and identified a recurrent subtype with high FTO expression and low HDAC1 expression across three independent gastric cancer (GC) cohorts, which we named the epigenetic-modification-dysregulated (EMD) subtype. Patients of the EMD subtype were featured with poor survival, stromal activation, and immune suppression. Extensive relevance to clinical characteristics was observed in the EMD subtype, including the Lauren classification, MSI status, histological grade, TNM stage, the Asian Cancer Research Group classification, and the immune/fibrotic classification. An EMD score was then constructed using WGCNA and ssGSEA algorithms, to precisely recognize the EMD subtype and indicate prognosis and response to immunotherapy in multiple independent GC cohorts. Correlations of the EMD score with tumor mutation burden, tumor purity, aneuploidy score, tumorigenic pathways, TME characteristics, and FTO/HDAC1 ratio were measured. In vitro experiments were performed to demonstrate the correlation between FTO and the epithelial–mesenchymal transition pathway, which suggested FTO as a targetable vulnerability for GC patients with a high EMD score. Altogether, by comprehensively analyzing the epigenetic modification patterns of 1518 GC patients, we identified a novel stromal-activated subtype with poor survival and resistance to immunotherapy, which might benefit from the combined immune checkpoint inhibition therapy with FTO inhibition.https://www.frontiersin.org/articles/10.3389/fphar.2022.868830/fullgastric cancerhistone modificationm6Atumor microenvironmentprognosisimmunotherapy |
| spellingShingle | Cheng Yuan Cheng Yuan Junchang Zhang Junchang Zhang Cuncan Deng Cuncan Deng Yujian Xia Bo Li Bo Li Sijun Meng Sijun Meng Xinghan Jin Xinghan Jin Lvjia Cheng Huafu Li Changhua Zhang Changhua Zhang Changhua Zhang Yulong He Yulong He Yulong He Yulong He Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer Frontiers in Pharmacology gastric cancer histone modification m6A tumor microenvironment prognosis immunotherapy |
| title | Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer |
| title_full | Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer |
| title_fullStr | Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer |
| title_full_unstemmed | Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer |
| title_short | Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer |
| title_sort | crosstalk of histone and rna modifications identified a stromal activated subtype with poor survival and resistance to immunotherapy in gastric cancer |
| topic | gastric cancer histone modification m6A tumor microenvironment prognosis immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.868830/full |
| work_keys_str_mv | AT chengyuan crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT chengyuan crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT junchangzhang crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT junchangzhang crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT cuncandeng crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT cuncandeng crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT yujianxia crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT boli crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT boli crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT sijunmeng crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT sijunmeng crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT xinghanjin crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT xinghanjin crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT lvjiacheng crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT huafuli crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT changhuazhang crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT changhuazhang crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT changhuazhang crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT yulonghe crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT yulonghe crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT yulonghe crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer AT yulonghe crosstalkofhistoneandrnamodificationsidentifiedastromalactivatedsubtypewithpoorsurvivalandresistancetoimmunotherapyingastriccancer |