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

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 () and Caigang Liu ()
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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
Haonan Li: Dalian University of Technology
Lisha Sun: Shengjing Hospital of China Medical University
Yang Liu: 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
Caigang Liu: Shengjing Hospital of China Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38097-1

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