KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer
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. Identify...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38097-1 |
| _version_ | 1797832016659480576 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jiawen Bu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:00:59Z |
| format | Article |
| id | doaj.art-4a6a3bc37dc04129b0d0a57674aa4a99 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T14:00:59Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4a6a3bc37dc04129b0d0a57674aa4a992023-05-07T11:17:26ZengNature PortfolioNature Communications2041-17232023-05-0114111810.1038/s41467-023-38097-1KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancerJiawen Bu0Yixiao Zhang1Sijin Wu2Haonan Li3Lisha Sun4Yang Liu5Xudong Zhu6Xinbo Qiao7Qingtian Ma8Chao Liu9Nan Niu10Jinqi Xue11Guanglei Chen12Yongliang Yang13Caigang Liu14Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversitySchool of Bioengineering, Dalian University of TechnologyCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversitySchool of Pharmaceutical Engineering, Shenyang Pharmaceutical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityCancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38097-1 |
| spellingShingle | 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 KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer Nature Communications |
| title | KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer |
| title_full | KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer |
| title_fullStr | KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer |
| title_full_unstemmed | KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer |
| title_short | KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer |
| title_sort | kk lc 1 as a therapeutic target to eliminate aldh stem cells in triple negative breast cancer |
| url | https://doi.org/10.1038/s41467-023-38097-1 |
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