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Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis

Author

Listed:
  • Zhenlei Zhang

    (Tianjin Medical University)

  • Yufan Wu

    (Tianjin Medical University)

  • Jinrong Fu

    (Southern Medical University)

  • Xiujie Yu

    (Tianjin Central Hospital of Gynecology and Obstetrics)

  • Yang Su

    (Southern University of Science and Technology)

  • Shikai Jia

    (Tianjin Medical University)

  • Huili Cheng

    (Tianjin Medical University)

  • Yan Shen

    (Tianjin Central Hospital of Gynecology and Obstetrics)

  • Xianghui He

    (Tianjin Medical University)

  • Kai Ren

    (Tianjin Medical University Cancer Institute and Hospital)

  • Xiangqian Zheng

    (Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer)

  • Haixia Guan

    (Southern Medical University)

  • Feng Rao

    (Southern University of Science and Technology)

  • Li Zhao

    (Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

Abstract

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

Suggested Citation

  • Zhenlei Zhang & Yufan Wu & Jinrong Fu & Xiujie Yu & Yang Su & Shikai Jia & Huili Cheng & Yan Shen & Xianghui He & Kai Ren & Xiangqian Zheng & Haixia Guan & Feng Rao & Li Zhao, 2024. "Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48173-9
    DOI: 10.1038/s41467-024-48173-9
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    References listed on IDEAS

    as
    1. Peitao Zhang & Haixia Guan & Shukai Yuan & Huili Cheng & Jian Zheng & Zhenlei Zhang & Yifan Liu & Yang Yu & Zhaowei Meng & Xiangqian Zheng & Li Zhao, 2022. "Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Peitao Zhang & Haixia Guan & Shukai Yuan & Huili Cheng & Jian Zheng & Zhenlei Zhang & Yifan Liu & Yang Yu & Zhaowei Meng & Xiangqian Zheng & Li Zhao, 2022. "Author Correction: Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    3. Achuth Padmanabhan & Nicholes Candelaria & Kwong-Kwok Wong & Bryan C. Nikolai & David M. Lonard & Bert W. O’Malley & JoAnne S. Richards, 2018. "USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    4. Yihan Peng & Qingchao Liao & Wei Tan & Changmin Peng & Zhaohua Hu & Yali Chen & Zhuqing Li & Jing Li & Bei Zhen & Wenge Zhu & Xiangpan Li & Yi Yao & Qibin Song & Chengsheng Liu & Xiangdong Qi & Fuchu , 2019. "The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
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