STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis
Abstract Background Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Methods Our objective is to elucidate the upregulation patte...
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2025-07-01
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| author | Fuda Xie Yang Lyu Bonan Chen Hoi Wing Leung Peiyao Yu Tiejun Feng Canbin Fang Alvin H.K. Cheung Bin Zhou Jianhui Jiang Ge Zhang Dazhi Xu Liang Li Chen Jiang Jianwu Chen Zhaocai Zhou Liwei An Bing Huang Kangmin Zhuang Xiaobei Luo Kam Tong Leung Ching Hei To Brigette BY Ma Chi Chun Wong William KK Wu Jun Yu Ka Fai To Wei Kang |
| author_facet | Fuda Xie Yang Lyu Bonan Chen Hoi Wing Leung Peiyao Yu Tiejun Feng Canbin Fang Alvin H.K. Cheung Bin Zhou Jianhui Jiang Ge Zhang Dazhi Xu Liang Li Chen Jiang Jianwu Chen Zhaocai Zhou Liwei An Bing Huang Kangmin Zhuang Xiaobei Luo Kam Tong Leung Ching Hei To Brigette BY Ma Chi Chun Wong William KK Wu Jun Yu Ka Fai To Wei Kang |
| author_sort | Fuda Xie |
| collection | DOAJ |
| description | Abstract Background Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Methods Our objective is to elucidate the upregulation pattern and molecular mechanisms of STK3 in advancing gastric cancer (GC) progression. The regulation of YAP1 on STK3 was assessed through a combination of bulk and single-cell RNA-sequencing, Western blot, ChIP-qPCR, gene knockout mouse models, and functional rescue assays. The oncogenic roles of STK3 were confirmed through subcutaneous xenograft formation models and functional assays including spheroid formation and organoid growth. The phosphorylated target of STK3 was revealed by co-immunoprecipitation and in vitro kinase assays. STK3-targeted drugs were screened out by molecular docking and cellular thermal shift assay (CETSA). Results Reduction of YAP1 significantly impaired STK3 expression at both mRNA and protein levels, and deletion of STK3 partially attenuated the oncogenic activity of YAP1. Notably, MNNG-induced tumors in Yap1 −/− Taz −/− mice exhibited decreased STK3 expression. Knockdown of STK3 led to reduced expression of stemness markers and xenograft growth, while sensitizing GC organoids and xenografts to 5-fluorouracil treatment. Mechanistically, the direct interaction between STK3 and GSK-3β promoted GSK-3β phosphorylation and β-catenin nuclear accumulation, and thus the activation of Wnt signaling. Furthermore, aminopterin demonstrates as a promising STK3-targeted small molecule with remarkable effectiveness in inhibiting GC cell malignance and xenograft growth. Conclusions STK3 was identified as a transcriptional target of YAP1, leading to enhanced DNA repair ability and stemness acquisition during GC progression by activating Wnt/β-catenin activity through GSK-3β degradation. Moreover, STK3-targeted therapy offered a novel approach to concur acquired chemo-resistance in GC patients. Graphical Abstract |
| format | Article |
| id | doaj-art-31a1de3a5cec483eb0ca94bebdb4f3e6 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj-art-31a1de3a5cec483eb0ca94bebdb4f3e62025-08-20T03:37:20ZengBMCMolecular Cancer1476-45982025-07-0124112010.1186/s12943-025-02391-xSTK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesisFuda Xie0Yang Lyu1Bonan Chen2Hoi Wing Leung3Peiyao Yu4Tiejun Feng5Canbin Fang6Alvin H.K. Cheung7Bin Zhou8Jianhui Jiang9Ge Zhang10Dazhi Xu11Liang Li12Chen Jiang13Jianwu Chen14Zhaocai Zhou15Liwei An16Bing Huang17Kangmin Zhuang18Xiaobei Luo19Kam Tong Leung20Ching Hei To21Brigette BY Ma22Chi Chun Wong23William KK Wu24Jun Yu25Ka Fai To26Wei Kang27Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anesthesiology, Renmin Hospital, Wuhan UniversityGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist UniversityDepartment of Gastric Surgery, Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan UniversityDepartment of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Nanfang Hospital and Basic Medical College, Southern Medical UniversityDepartment of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat- Sen University Cancer CenterDepartment of Burn and Plastic Surgery, General Hospital of Southern Theater Command, PLAState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan UniversityDepartment of Stomatology, Department of Biochemistry and Molecular Biology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineGuangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical UniversityGuangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical UniversityGuangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical UniversityDepartment of Pediatrics, The Chinese University of Hong KongDepartment of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong KongDepartment of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong KongInstitute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong KongDepartment of Anaesthesia and Intensive Care, The Chinese University of Hong KongInstitute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongDepartment of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongAbstract Background Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Methods Our objective is to elucidate the upregulation pattern and molecular mechanisms of STK3 in advancing gastric cancer (GC) progression. The regulation of YAP1 on STK3 was assessed through a combination of bulk and single-cell RNA-sequencing, Western blot, ChIP-qPCR, gene knockout mouse models, and functional rescue assays. The oncogenic roles of STK3 were confirmed through subcutaneous xenograft formation models and functional assays including spheroid formation and organoid growth. The phosphorylated target of STK3 was revealed by co-immunoprecipitation and in vitro kinase assays. STK3-targeted drugs were screened out by molecular docking and cellular thermal shift assay (CETSA). Results Reduction of YAP1 significantly impaired STK3 expression at both mRNA and protein levels, and deletion of STK3 partially attenuated the oncogenic activity of YAP1. Notably, MNNG-induced tumors in Yap1 −/− Taz −/− mice exhibited decreased STK3 expression. Knockdown of STK3 led to reduced expression of stemness markers and xenograft growth, while sensitizing GC organoids and xenografts to 5-fluorouracil treatment. Mechanistically, the direct interaction between STK3 and GSK-3β promoted GSK-3β phosphorylation and β-catenin nuclear accumulation, and thus the activation of Wnt signaling. Furthermore, aminopterin demonstrates as a promising STK3-targeted small molecule with remarkable effectiveness in inhibiting GC cell malignance and xenograft growth. Conclusions STK3 was identified as a transcriptional target of YAP1, leading to enhanced DNA repair ability and stemness acquisition during GC progression by activating Wnt/β-catenin activity through GSK-3β degradation. Moreover, STK3-targeted therapy offered a novel approach to concur acquired chemo-resistance in GC patients. Graphical Abstracthttps://doi.org/10.1186/s12943-025-02391-xSTK3YAP1Wnt signalingGastric cancer |
| spellingShingle | Fuda Xie Yang Lyu Bonan Chen Hoi Wing Leung Peiyao Yu Tiejun Feng Canbin Fang Alvin H.K. Cheung Bin Zhou Jianhui Jiang Ge Zhang Dazhi Xu Liang Li Chen Jiang Jianwu Chen Zhaocai Zhou Liwei An Bing Huang Kangmin Zhuang Xiaobei Luo Kam Tong Leung Ching Hei To Brigette BY Ma Chi Chun Wong William KK Wu Jun Yu Ka Fai To Wei Kang STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis Molecular Cancer STK3 YAP1 Wnt signaling Gastric cancer |
| title | STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis |
| title_full | STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis |
| title_fullStr | STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis |
| title_full_unstemmed | STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis |
| title_short | STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis |
| title_sort | stk3 is a transcriptional target of yap1 and a hub component in the crosstalk between hippo and wnt signaling pathways during gastric carcinogenesis |
| topic | STK3 YAP1 Wnt signaling Gastric cancer |
| url | https://doi.org/10.1186/s12943-025-02391-x |
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