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Updated: Jun 26, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis

Zhenlei Zhang1, Yufan Wu1, Jinrong Fu2

  • 1Department of Thyroid and Neck Oncology, 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, Tianjin, China.

Nature Communications
|May 15, 2024
PubMed

Insights

BRAFV600E-driven tumors dedifferentiate via USP15 stabilizing TBX3, a developmental factor. Reactivating this axis drives tumorigenesis, while its deletion causes tumor redifferentiation, highlighting a key proteostatic mechanism.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Cancer Biology

Background:

  • MAPK pathway activation, particularly BRAFV600E, drives tumorigenesis by inducing epithelial dedifferentiation.
  • The precise mechanisms by which lineage differentiation is reprogrammed during tumorigenesis remain largely unexplored.

Purpose of the Study:

  • To investigate the role of developmental factors in BRAF/MAPK-mediated dedifferentiation and tumorigenesis.
  • To elucidate the proteostatic mechanisms underlying pathological transformation driven by the MAPK pathway.

Main Methods:

  • Utilized knockout models (Usp15, Tbx3) to assess their impact on BRAFV600E-driven tumor development.
  • Examined the interplay between BRAF/MAPK signaling, USP15, and TBX3 during embryonic development and tumorigenesis.
  • Analyzed tumor differentiation markers and clinical data correlating USP15 and TBX3 expression with BRAFV600E and prognosis.

Main Results:

  • Demonstrated that proteostatic reactivation of the developmental factor TBX3 drives BRAF/MAPK-mediated dedifferentiation and tumorigenesis.
  • Showed that BRAF/MAPK upregulates USP15 to stabilize TBX3 during embryonic development, a process reactivated in tumors.
  • Found that Usp15 knockout inhibits BRAFV600E-driven tumor development in a Tbx3-dependent manner, with deletion leading to tumor redifferentiation and disrupted thyroid folliculogenesis.

Conclusions:

  • The USP15-TBX3 axis is a critical downstream effector of BRAF/MAPK signaling, crucial for both developmental homeostasis and pathological transformation.
  • Tumorigenesis relies on epithelial dedifferentiation achieved through the reinitiation of embryonic regulatory programs.
  • USP15 stabilization of TBX3 represents a key proteostatic mechanism linking developmental pathways to cancer progression, offering potential therapeutic targets.

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