Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming
Advanced colorectal cancer (CRC) exhibits weak responses to multiple therapies, primarily due to the presence of cancer stem cells (CSCs), which drive high recurrence rates, metastasis, and drug resistance. We have previously systematically conducted CSC-targeted compound discovery and evaluation st...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | The Innovation |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666675825000347 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761261810614272 |
|---|---|
| author | Suyao Li Wenrui Zhao Quanlin An Lei Wang Mengxuan Zhu Junjie Ni Xuan Huang Yudong Jiang Min Li Jiayun Hou Yiyi Yu Shan Yu Lai Wei Heng Jiao Tianshu Liu Xin Cao |
| author_facet | Suyao Li Wenrui Zhao Quanlin An Lei Wang Mengxuan Zhu Junjie Ni Xuan Huang Yudong Jiang Min Li Jiayun Hou Yiyi Yu Shan Yu Lai Wei Heng Jiao Tianshu Liu Xin Cao |
| author_sort | Suyao Li |
| collection | DOAJ |
| description | Advanced colorectal cancer (CRC) exhibits weak responses to multiple therapies, primarily due to the presence of cancer stem cells (CSCs), which drive high recurrence rates, metastasis, and drug resistance. We have previously systematically conducted CSC-targeted compound discovery and evaluation studies to inhibit CSC-mediated tumorigenesis and metastasis. Here, we identified ZSH-512, a novel synthetic retinoid that selectively targets retinoic acid receptor (RAR)γ, demonstrating its ability to effectively inhibit CRC-CSCs and patient-derived organoids (PDOs) in vitro and significantly reduce CSC-mediated tumor formation and liver metastasis in mouse models without noticeable toxicity. Mechanistically, integrated analysis of Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) revealed that ZSH-512 exerted its effect by modulating the RARγ-KDM3A axis to mediate epigenetic reprogramming and broadly suppress stemness-related signaling pathways, including Wnt, Hippo, and Hedgehog. ZSH-512 efficiently inhibited tumorigenesis in CRC-patient-derived tumor xenografts (PDXs) with high KDM3A expression, suggesting KDM3A as a potential predictive biomarker. Collectively, ZSH-512 is a promising therapeutic candidate for targeting CRC-CSCs with high efficacy. |
| format | Article |
| id | doaj-art-91bf3eb3a99e433ca266a6f227a05cea |
| institution | DOAJ |
| issn | 2666-6758 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Innovation |
| spelling | doaj-art-91bf3eb3a99e433ca266a6f227a05cea2025-08-20T03:06:05ZengElsevierThe Innovation2666-67582025-04-016410083110.1016/j.xinn.2025.100831Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogrammingSuyao Li0Wenrui Zhao1Quanlin An2Lei Wang3Mengxuan Zhu4Junjie Ni5Xuan Huang6Yudong Jiang7Min Li8Jiayun Hou9Yiyi Yu10Shan Yu11Lai Wei12Heng Jiao13Tianshu Liu14Xin Cao15Department of Medical Oncology, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Medical Oncology, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 20032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of Medical Oncology, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 20032, ChinaDepartment of Medical Oncology, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 20032, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 20032, China; Corresponding authorDepartment of Medical Oncology, Shanghai Key Laboratory of Oncology Target Discovery and Antibody Drug Development, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 20032, China; Corresponding authorInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 20032, China; Corresponding authorAdvanced colorectal cancer (CRC) exhibits weak responses to multiple therapies, primarily due to the presence of cancer stem cells (CSCs), which drive high recurrence rates, metastasis, and drug resistance. We have previously systematically conducted CSC-targeted compound discovery and evaluation studies to inhibit CSC-mediated tumorigenesis and metastasis. Here, we identified ZSH-512, a novel synthetic retinoid that selectively targets retinoic acid receptor (RAR)γ, demonstrating its ability to effectively inhibit CRC-CSCs and patient-derived organoids (PDOs) in vitro and significantly reduce CSC-mediated tumor formation and liver metastasis in mouse models without noticeable toxicity. Mechanistically, integrated analysis of Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) revealed that ZSH-512 exerted its effect by modulating the RARγ-KDM3A axis to mediate epigenetic reprogramming and broadly suppress stemness-related signaling pathways, including Wnt, Hippo, and Hedgehog. ZSH-512 efficiently inhibited tumorigenesis in CRC-patient-derived tumor xenografts (PDXs) with high KDM3A expression, suggesting KDM3A as a potential predictive biomarker. Collectively, ZSH-512 is a promising therapeutic candidate for targeting CRC-CSCs with high efficacy.http://www.sciencedirect.com/science/article/pii/S2666675825000347ZSH-512colorectal cancerKDM3Acancer stem celltumor-repopulating cellretinoid |
| spellingShingle | Suyao Li Wenrui Zhao Quanlin An Lei Wang Mengxuan Zhu Junjie Ni Xuan Huang Yudong Jiang Min Li Jiayun Hou Yiyi Yu Shan Yu Lai Wei Heng Jiao Tianshu Liu Xin Cao Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming The Innovation ZSH-512 colorectal cancer KDM3A cancer stem cell tumor-repopulating cell retinoid |
| title | Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming |
| title_full | Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming |
| title_fullStr | Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming |
| title_full_unstemmed | Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming |
| title_short | Novel cancer stem cell-targeted retinoid ZSH-512 impedes colorectal cancer progress via KDM3A-mediated epigenetic reprogramming |
| title_sort | novel cancer stem cell targeted retinoid zsh 512 impedes colorectal cancer progress via kdm3a mediated epigenetic reprogramming |
| topic | ZSH-512 colorectal cancer KDM3A cancer stem cell tumor-repopulating cell retinoid |
| url | http://www.sciencedirect.com/science/article/pii/S2666675825000347 |
| work_keys_str_mv | AT suyaoli novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT wenruizhao novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT quanlinan novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT leiwang novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT mengxuanzhu novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT junjieni novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT xuanhuang novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT yudongjiang novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT minli novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT jiayunhou novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT yiyiyu novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT shanyu novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT laiwei novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT hengjiao novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT tianshuliu novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming AT xincao novelcancerstemcelltargetedretinoidzsh512impedescolorectalcancerprogressviakdm3amediatedepigeneticreprogramming |