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<p>Fatty acid metabolism is critical for tumor progression, supplying bioenergetic and biosynthetic substrates to rapidly proliferating cancer cells. However, the precise mechanisms by which fatty acid metabolism influences breast cancer progression remain unclear. In this study, we aimed to explore the molecular mechanism by which C-Jun activation domain-binding protein-1 (<i>JAB1</i>) promotes breast cancer progression through regulating fatty acid metabolism. The JAB1 is identified as an oncogene in breast cancer. JAB1 promotes cell proliferation, invasion, and stemness by stabilizing CUL4B protein. Mechanistically, JAB1 forms a transcriptional repressor complex with the Cullin 4B-Ring E3 ligase (CRL4B) complex, co-occupying the promoters of key fatty acid metabolism genes, <i>PPARG</i> and <i>ACSL5</i>, thus leading to their transcriptional repression. This activates fatty acid metabolism, increasing mitochondrial oxygen consumption and supporting the energetic demands of tumor cells. Notably, <i>JAB1</i> inhibition reverses chemotherapy resistance associated with <i>CUL4B</i> overexpression. These findings underscore the pivotal role of JAB1 in regulating breast cancer progression and indicate that JAB1 inhibitors could serve as promising therapeutics for patients with elevated <i>CUL4B</i> expression.</p>

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JAB1/CRL4B complex represses PPARG/ACSL5 expression to promote breast tumorigenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Ting Hu,
  • Tianyu Ma,
  • Miaomiao Huo,
  • Jiaxiang Liu,
  • Die Zhang,
  • Yu Li,
  • Jinyuan Chang,
  • Min Zhang,
  • Yinuo Wang,
  • Tianyang Gao,
  • Baowen Yuan,
  • Siqi Wang,
  • Qing Li,
  • Xiaoqi Ma,
  • Jingyao Zhang,
  • Wei Huang,
  • Yan Wang

摘要

Fatty acid metabolism is critical for tumor progression, supplying bioenergetic and biosynthetic substrates to rapidly proliferating cancer cells. However, the precise mechanisms by which fatty acid metabolism influences breast cancer progression remain unclear. In this study, we aimed to explore the molecular mechanism by which C-Jun activation domain-binding protein-1 (JAB1) promotes breast cancer progression through regulating fatty acid metabolism. The JAB1 is identified as an oncogene in breast cancer. JAB1 promotes cell proliferation, invasion, and stemness by stabilizing CUL4B protein. Mechanistically, JAB1 forms a transcriptional repressor complex with the Cullin 4B-Ring E3 ligase (CRL4B) complex, co-occupying the promoters of key fatty acid metabolism genes, PPARG and ACSL5, thus leading to their transcriptional repression. This activates fatty acid metabolism, increasing mitochondrial oxygen consumption and supporting the energetic demands of tumor cells. Notably, JAB1 inhibition reverses chemotherapy resistance associated with CUL4B overexpression. These findings underscore the pivotal role of JAB1 in regulating breast cancer progression and indicate that JAB1 inhibitors could serve as promising therapeutics for patients with elevated CUL4B expression.