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Elevated FBXL6 activates ATAD3A through K63-linked polyubiquitination and promotes the malignant progression of TNBC

Yao Wu1, Jing Pan2, Jingjing Wei3

  • 1Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.

International Journal of Biological Macromolecules
|September 20, 2025
PubMed

Insights

Triple-negative breast cancer (TNBC) is hard to treat. Our study shows ATPase family AAA domain-containing protein 3A (ATAD3A) drives TNBC by stabilizing through FBXL6, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Triple-negative breast cancer (TNBC) lacks targeted therapies due to undefined molecular drivers.
  • Identifying novel molecular targets is critical for advancing TNBC treatment strategies.

Purpose of the Study:

  • To investigate the role of ATPase family AAA domain-containing protein 3A (ATAD3A) in TNBC progression.
  • To elucidate the regulatory mechanism of ATAD3A in TNBC.
  • To evaluate the FBXL6-ATAD3A axis as a potential therapeutic target for TNBC.

Main Methods:

  • Analysis of TCGA database for ATAD3A expression in TNBC.
  • Immunohistochemistry (IHC) and western blotting to assess ATAD3A protein levels.
  • In vitro and in vivo experiments involving genetic depletion of ATAD3A.
  • Investigation of the interaction between FBXL6 and ATAD3A and its effect on ATAD3A ubiquitination and stability.
  • Assessment of aerobic glycolysis pathways.

Main Results:

  • ATAD3A is significantly overexpressed in TNBC tissues and correlates with poor clinical outcomes.
  • Genetic depletion of ATAD3A markedly inhibits TNBC tumor growth in cellular and animal models.
  • FBXL6 directly targets ATAD3A, promoting K63-linked polyubiquitination and stabilization of ATAD3A.
  • The FBXL6-ATAD3A interaction activates aerobic glycolysis, enhancing tumor malignancy.
  • Co-expression of FBXL6 and ATAD3A in clinical specimens predicts a poor prognosis.

Conclusions:

  • The FBXL6-ATAD3A axis is a critical driver of TNBC progression.
  • FBXL6-mediated stabilization of ATAD3A promotes TNBC malignancy via aerobic glycolysis.
  • Targeting the FBXL6-ATAD3A axis represents a promising therapeutic strategy for TNBC.
Keywords:
ATAD3AAerobic glycolysisFBXL6TNBCUbiquitination

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