VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300
Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEADs. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-...
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eLife Sciences Publications Ltd
2025-05-01
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| Online Access: | https://elifesciences.org/articles/98386 |
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| author | Susu Guo Xiaodi Hu Jennifer L Cotton Lifang Ma Qi Li Jiangtao Cui Yongjie Wang Ritesh P Thakare Zhipeng Tao Y Tony Ip Xu Wu Jiayi Wang Junhao Mao |
| author_facet | Susu Guo Xiaodi Hu Jennifer L Cotton Lifang Ma Qi Li Jiangtao Cui Yongjie Wang Ritesh P Thakare Zhipeng Tao Y Tony Ip Xu Wu Jiayi Wang Junhao Mao |
| author_sort | Susu Guo |
| collection | DOAJ |
| description | Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEADs. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in human spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1 the fusion proteins are potent activators of TEAD-dependent transcription, and the function of these fusion proteins does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase EP300 to control TEAD-mediated transcriptional and epigenetic landscapes. We show that small-molecule EP300 inhibition can suppress fusion protein-induced oncogenic transformation both in vitro and in vivo in mouse models. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations. |
| format | Article |
| id | doaj-art-5337db03441e40b8a9611a3f6f636884 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-5337db03441e40b8a9611a3f6f6368842025-08-20T02:14:23ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.98386VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300Susu Guo0https://orcid.org/0000-0002-7481-6884Xiaodi Hu1Jennifer L Cotton2https://orcid.org/0000-0003-0106-1801Lifang Ma3Qi Li4Jiangtao Cui5Yongjie Wang6Ritesh P Thakare7Zhipeng Tao8Y Tony Ip9https://orcid.org/0000-0003-4370-7906Xu Wu10Jiayi Wang11https://orcid.org/0000-0003-1688-2864Junhao Mao12https://orcid.org/0000-0003-1980-1177Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United StatesDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United StatesDepartment of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, United StatesDepartment of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United StatesCutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United StatesProgram in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, United StatesCutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, United StatesDepartment of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, United StatesStudies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEADs. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in human spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1 the fusion proteins are potent activators of TEAD-dependent transcription, and the function of these fusion proteins does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase EP300 to control TEAD-mediated transcriptional and epigenetic landscapes. We show that small-molecule EP300 inhibition can suppress fusion protein-induced oncogenic transformation both in vitro and in vivo in mouse models. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.https://elifesciences.org/articles/98386VGLL2TEADHIPPOYAPNCOA2EP300 |
| spellingShingle | Susu Guo Xiaodi Hu Jennifer L Cotton Lifang Ma Qi Li Jiangtao Cui Yongjie Wang Ritesh P Thakare Zhipeng Tao Y Tony Ip Xu Wu Jiayi Wang Junhao Mao VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 eLife VGLL2 TEAD HIPPO YAP NCOA2 EP300 |
| title | VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 |
| title_full | VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 |
| title_fullStr | VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 |
| title_full_unstemmed | VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 |
| title_short | VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 |
| title_sort | vgll2 and tead1 fusion proteins identified in human sarcoma drive yap taz independent tumorigenesis by engaging ep300 |
| topic | VGLL2 TEAD HIPPO YAP NCOA2 EP300 |
| url | https://elifesciences.org/articles/98386 |
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