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KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer

Author

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  • Jiawen Bu

    (Shengjing Hospital of China Medical University)

  • Yixiao Zhang

    (Shengjing Hospital of China Medical University)

  • Sijin Wu

    (Shengjing Hospital of China Medical University
    International Biomedical Industrial Park (Phase II) 3F)

  • Haonan Li

    (Dalian University of Technology)

  • Lisha Sun

    (Shengjing Hospital of China Medical University)

  • Yang Liu

    (Shenyang Pharmaceutical University
    Shenyang Pharmaceutical University)

  • Xudong Zhu

    (Shengjing Hospital of China Medical University)

  • Xinbo Qiao

    (Shengjing Hospital of China Medical University)

  • Qingtian Ma

    (Shengjing Hospital of China Medical University)

  • Chao Liu

    (Shengjing Hospital of China Medical University)

  • Nan Niu

    (Shengjing Hospital of China Medical University)

  • Jinqi Xue

    (Shengjing Hospital of China Medical University)

  • Guanglei Chen

    (Shengjing Hospital of China Medical University)

  • Yongliang Yang

    (Shengjing Hospital of China Medical University
    Dalian University of Technology)

  • Caigang Liu

    (Shengjing Hospital of China Medical University)

Abstract

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

Suggested Citation

  • Jiawen Bu & Yixiao Zhang & Sijin Wu & Haonan Li & Lisha Sun & Yang Liu & Xudong Zhu & Xinbo Qiao & Qingtian Ma & Chao Liu & Nan Niu & Jinqi Xue & Guanglei Chen & Yongliang Yang & Caigang Liu, 2023. "KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38097-1
    DOI: 10.1038/s41467-023-38097-1
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    1. Fuping Wen & Yi Han & Hui Zhang & Zhangting Zhao & Wenjia Wang & Fan Chen & Weimin Qin & Junyi Ju & Liwei An & Yan Meng & Jie Yang & Yang Tang & Yun Zhao & Huanhu Zhang & Feng Li & Wenqi Bai & Yuanzhi, 2024. "Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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