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Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis
Nature Communications ( IF 16.6 ) Pub Date : 2024-05-15 , DOI: 10.1038/s41467-024-48173-9
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

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.



中文翻译:

发育转录因子 TBX3 的蛋白抑制再激活驱动 BRAF/MAPK 介导的肿瘤发生

MAPK 通路驱动的肿瘤发生通常由 BRAF V600E诱导,依赖于上皮去分化。然而,谱系分化事件如何重新编程仍有待探索。在这里,我们证明发育因子 TBX3 的蛋白抑制再激活是 BRAF/MAPK 介导的去分化和肿瘤发生的原因。在胚胎发育过程中,BRAF/MAPK 上调 USP15 以稳定 TBX3,从而通过抑制分化来协调器官发生。 USP15-TBX3轴在肿瘤发生过程中被重新激活,并且Usp15敲除以Tbx3依赖性方式抑制BRAF V600E驱动的肿瘤发展。删除 Tbx3 或 Usp15 会导致肿瘤再分化,这与它们在发育过程中的过度分化趋势相似,例如甲状腺滤泡发生中断和 Tpo、Nis、Tg 等分化因子升高。临床相关性突出,因为 USP15 和 TBX3 都与 BRAF V600E特征和不良肿瘤预后高度相关。因此,USP15稳定的TBX3代表了BRAF/MAPK介导的发育稳态和病理转化下游的关键蛋白抑制机制,支持肿瘤发生很大程度上依赖于通过胚胎调节程序重新启动实现的上皮去分化。

更新日期:2024-05-15
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