RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer
Abstract Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon‐γ (IFN‐γ) signaling, in which IFN‐γ is linked to improved responsiveness to ICIs. Herein, th...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410806 |
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| author | Dongjun Jang Chanwoong Hwa Seoyeon Kim Jaeik Oh Seungjae Shin Soo‐Jin Lee Jiwon Kim Sang Eun Lee Yoojin Yang Dohee Kim Seoho Lee Hae Rim Jung Yumi Oh Kyunggon Kim Hye Seung Lee Joon‐Yong An Sung‐Yup Cho |
| author_facet | Dongjun Jang Chanwoong Hwa Seoyeon Kim Jaeik Oh Seungjae Shin Soo‐Jin Lee Jiwon Kim Sang Eun Lee Yoojin Yang Dohee Kim Seoho Lee Hae Rim Jung Yumi Oh Kyunggon Kim Hye Seung Lee Joon‐Yong An Sung‐Yup Cho |
| author_sort | Dongjun Jang |
| collection | DOAJ |
| description | Abstract Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon‐γ (IFN‐γ) signaling, in which IFN‐γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6‐methyladenosine (m6A) modifications in regulation of IFN‐γ signaling and the responsiveness to ICIs are unveiled. The m6A‐binding protein YTH N6‐methyladenosine RNA‐binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN‐γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN‐γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN‐γ signaling, leading to reduced RNA stability and consequent downregulation of IFN‐γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor‐infiltrating lymphocytes, which are attributed to the augmentation of IFN‐γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN‐γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy. |
| format | Article |
| id | doaj-art-09c893c5010343348773614b4710f896 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-09c893c5010343348773614b4710f8962025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202410806RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric CancerDongjun Jang0Chanwoong Hwa1Seoyeon Kim2Jaeik Oh3Seungjae Shin4Soo‐Jin Lee5Jiwon Kim6Sang Eun Lee7Yoojin Yang8Dohee Kim9Seoho Lee10Hae Rim Jung11Yumi Oh12Kyunggon Kim13Hye Seung Lee14Joon‐Yong An15Sung‐Yup Cho16Department of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaL‐HOPE Program for Community‐Based Total Learning Health Systems Korea University Seoul 02841 South KoreaL‐HOPE Program for Community‐Based Total Learning Health Systems Korea University Seoul 02841 South KoreaDepartment of Translational Medicine Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaMedical Research Center, Genomic Medicine Institute Seoul National University College of Medicine Seoul 03080 South KoreaMedical Research Center, Genomic Medicine Institute Seoul National University College of Medicine Seoul 03080 South KoreaDepartment of Biomedical Sciences University of Ulsan College of Medicine Seoul 05505 South KoreaDepartment of Pathology Seoul National University College of Medicine Seoul 03080 South KoreaL‐HOPE Program for Community‐Based Total Learning Health Systems Korea University Seoul 02841 South KoreaDepartment of Biomedical Sciences Seoul National University College of Medicine Seoul 03080 South KoreaAbstract Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon‐γ (IFN‐γ) signaling, in which IFN‐γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6‐methyladenosine (m6A) modifications in regulation of IFN‐γ signaling and the responsiveness to ICIs are unveiled. The m6A‐binding protein YTH N6‐methyladenosine RNA‐binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN‐γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN‐γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN‐γ signaling, leading to reduced RNA stability and consequent downregulation of IFN‐γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor‐infiltrating lymphocytes, which are attributed to the augmentation of IFN‐γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN‐γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.https://doi.org/10.1002/advs.202410806cancer immunitygastric cancerinterferon‐γ signalingN6‐methyladenosineYTHDF proteins |
| spellingShingle | Dongjun Jang Chanwoong Hwa Seoyeon Kim Jaeik Oh Seungjae Shin Soo‐Jin Lee Jiwon Kim Sang Eun Lee Yoojin Yang Dohee Kim Seoho Lee Hae Rim Jung Yumi Oh Kyunggon Kim Hye Seung Lee Joon‐Yong An Sung‐Yup Cho RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer Advanced Science cancer immunity gastric cancer interferon‐γ signaling N6‐methyladenosine YTHDF proteins |
| title | RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer |
| title_full | RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer |
| title_fullStr | RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer |
| title_full_unstemmed | RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer |
| title_short | RNA N6‐Methyladenosine‐Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN‐γ Signaling in Gastric Cancer |
| title_sort | rna n6 methyladenosine binding protein ythdfs redundantly attenuate cancer immunity by downregulating ifn γ signaling in gastric cancer |
| topic | cancer immunity gastric cancer interferon‐γ signaling N6‐methyladenosine YTHDF proteins |
| url | https://doi.org/10.1002/advs.202410806 |
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