EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma
Abstract T-cell lymphoma (TCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that is associated with a poor prognosis. Although HDAC inhibitors have been approved for TCL treatment for several years, their expected therapeutic efficacy remains unmet in some patients. In this study, we discovered t...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07775-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761018824097792 |
|---|---|
| author | Jiajin Wu Dingyao Hu Hui Yu Dedao Wang Yingying Ye Jiaowu Cao Tao Pan Lan Mi Yuqin Song Meng Wu Lingyan Ping Jun Zhu |
| author_facet | Jiajin Wu Dingyao Hu Hui Yu Dedao Wang Yingying Ye Jiaowu Cao Tao Pan Lan Mi Yuqin Song Meng Wu Lingyan Ping Jun Zhu |
| author_sort | Jiajin Wu |
| collection | DOAJ |
| description | Abstract T-cell lymphoma (TCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that is associated with a poor prognosis. Although HDAC inhibitors have been approved for TCL treatment for several years, their expected therapeutic efficacy remains unmet in some patients. In this study, we discovered that TCL tumor cells develop resistance to HDAC inhibitor treatment by upregulating the methylation of lysine 27 on histone H3 (H3K27me3) levels. Furthermore, we confirmed the pharmacological efficacy of the EZH2 inhibitor SHR2554 and demonstrated a synergistic effect when combined with the HDAC inhibitor Chidamide through commercial TCL cell lines, in vivo cell-derived xenograft, and patient-derived xenograft cancer models. We inferred that STAT1 was the key driver of the synergistic effect using RNA-seq and ChIP-seq analysis. Our findings provide sufficient preclinical evidence in support of a potential combination therapy strategy for TCL patients. |
| format | Article |
| id | doaj-art-3b71cbdee01f4097808e1c4483c808ca |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-3b71cbdee01f4097808e1c4483c808ca2025-08-20T03:06:09ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111210.1038/s41419-025-07775-xEZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphomaJiajin Wu0Dingyao Hu1Hui Yu2Dedao Wang3Yingying Ye4Jiaowu Cao5Tao Pan6Lan Mi7Yuqin Song8Meng Wu9Lingyan Ping10Jun Zhu11Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & InstituteAbstract T-cell lymphoma (TCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that is associated with a poor prognosis. Although HDAC inhibitors have been approved for TCL treatment for several years, their expected therapeutic efficacy remains unmet in some patients. In this study, we discovered that TCL tumor cells develop resistance to HDAC inhibitor treatment by upregulating the methylation of lysine 27 on histone H3 (H3K27me3) levels. Furthermore, we confirmed the pharmacological efficacy of the EZH2 inhibitor SHR2554 and demonstrated a synergistic effect when combined with the HDAC inhibitor Chidamide through commercial TCL cell lines, in vivo cell-derived xenograft, and patient-derived xenograft cancer models. We inferred that STAT1 was the key driver of the synergistic effect using RNA-seq and ChIP-seq analysis. Our findings provide sufficient preclinical evidence in support of a potential combination therapy strategy for TCL patients.https://doi.org/10.1038/s41419-025-07775-x |
| spellingShingle | Jiajin Wu Dingyao Hu Hui Yu Dedao Wang Yingying Ye Jiaowu Cao Tao Pan Lan Mi Yuqin Song Meng Wu Lingyan Ping Jun Zhu EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma Cell Death and Disease |
| title | EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma |
| title_full | EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma |
| title_fullStr | EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma |
| title_full_unstemmed | EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma |
| title_short | EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma |
| title_sort | ezh2 inhibitor shr2554 enhances the anti tumor efficacy of hdac inhibitor chidamide through stat1 in t cell lymphoma |
| url | https://doi.org/10.1038/s41419-025-07775-x |
| work_keys_str_mv | AT jiajinwu ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT dingyaohu ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT huiyu ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT dedaowang ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT yingyingye ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT jiaowucao ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT taopan ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT lanmi ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT yuqinsong ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT mengwu ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT lingyanping ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma AT junzhu ezh2inhibitorshr2554enhancestheantitumorefficacyofhdacinhibitorchidamidethroughstat1intcelllymphoma |