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<p>Breast cancer stem cells are recognized as the key factors contributing to breast cancer progression and drug resistance, while polarity proteins play a pivotal role in regulating the fate of cancer stem cells and the progression of malignant tumors. However, the function of the polarity protein MALS3 in modulating cancer stem cell-like properties remains unclear. Here, we identify that the loss of the polarity protein MALS3 disrupts the homeostasis of mammary epithelial cells while increasing breast cancer stem cell-like properties. Mechanistically, MALS3 utilizes its L27 domain to mediate the interaction between the kinase LATS1 and TAZ, thereby promoting the phosphorylation of TAZ. Furthermore, MALS3 can recruit the E3 ubiquitin ligase TRIM29 to interact with TAZ. Subsequently, TRIM29 ultimately drives the degradation of TAZ via K48-linked polyubiquitination, and this regulatory process operates independently of the classical Hippo signaling pathway. We discover that the MALS3 upregulator mirtazapine suppresses stem cell-like properties and effectively enhances tumor sensitivity to doxorubicin in vivo. This study reveals the molecular mechanism by which the polarity protein MALS3 regulates breast cancer stem cell-like properties and suggests that MALS3 upregulation via mirtazapine may enhance tumor sensitivity to chemotherapeutic drugs.</p>

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Polarity protein MALS3 suppresses breast cancer stem cell-like properties by promoting TAZ inactivation and ubiquitination-dependent degradation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月21日

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  • Yangyang Shang,
  • Xinyi Gan,
  • Bixia Tian,
  • Yazhao Li,
  • Ruiqi Wang,
  • Ying Wang,
  • Nanxin Liu,
  • Huiwen Zhang,
  • Jingyue Zhang,
  • Shaoran Song,
  • Zejian Yang,
  • Yuchen Xie,
  • Rumeng Pan,
  • Juan Li,
  • Bo Wang,
  • Zhangjun Song,
  • Yu Ren,
  • Jie Liu,
  • Peijun Liu

摘要

Breast cancer stem cells are recognized as the key factors contributing to breast cancer progression and drug resistance, while polarity proteins play a pivotal role in regulating the fate of cancer stem cells and the progression of malignant tumors. However, the function of the polarity protein MALS3 in modulating cancer stem cell-like properties remains unclear. Here, we identify that the loss of the polarity protein MALS3 disrupts the homeostasis of mammary epithelial cells while increasing breast cancer stem cell-like properties. Mechanistically, MALS3 utilizes its L27 domain to mediate the interaction between the kinase LATS1 and TAZ, thereby promoting the phosphorylation of TAZ. Furthermore, MALS3 can recruit the E3 ubiquitin ligase TRIM29 to interact with TAZ. Subsequently, TRIM29 ultimately drives the degradation of TAZ via K48-linked polyubiquitination, and this regulatory process operates independently of the classical Hippo signaling pathway. We discover that the MALS3 upregulator mirtazapine suppresses stem cell-like properties and effectively enhances tumor sensitivity to doxorubicin in vivo. This study reveals the molecular mechanism by which the polarity protein MALS3 regulates breast cancer stem cell-like properties and suggests that MALS3 upregulation via mirtazapine may enhance tumor sensitivity to chemotherapeutic drugs.