Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair
Abstract FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01374-0 |
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| _version_ | 1825197644375392256 |
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| author | Shishi Tao Yue Pu Eun Ju Yang Guowen Ren Changxiang Shi Li-Jie Chen Liang Chen Joong Sup Shim |
| author_facet | Shishi Tao Yue Pu Eun Ju Yang Guowen Ren Changxiang Shi Li-Jie Chen Liang Chen Joong Sup Shim |
| author_sort | Shishi Tao |
| collection | DOAJ |
| description | Abstract FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss. |
| format | Article |
| id | doaj-art-94991c53bc334479a04ce58ce2b760de |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-94991c53bc334479a04ce58ce2b760de2025-02-09T12:14:11ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157116718310.1038/s12276-024-01374-0Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repairShishi Tao0Yue Pu1Eun Ju Yang2Guowen Ren3Changxiang Shi4Li-Jie Chen5Liang Chen6Joong Sup Shim7Cancer Centre, Faculty of Health Sciences, University of MacauCancer Centre, Faculty of Health Sciences, University of MacauCancer Centre, Faculty of Health Sciences, University of MacauInstitute of Cancer Research, Shenzhen Bay LaboratoryNanjing Key Laboratory of Female Fertility Preservation and Restoration, Nanjing Women and Children’s Healthcare Institute, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital)Cancer Centre, Faculty of Health Sciences, University of MacauShenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesCancer Centre, Faculty of Health Sciences, University of MacauAbstract FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss.https://doi.org/10.1038/s12276-024-01374-0 |
| spellingShingle | Shishi Tao Yue Pu Eun Ju Yang Guowen Ren Changxiang Shi Li-Jie Chen Liang Chen Joong Sup Shim Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair Experimental and Molecular Medicine |
| title | Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair |
| title_full | Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair |
| title_fullStr | Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair |
| title_full_unstemmed | Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair |
| title_short | Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair |
| title_sort | inhibition of gsk3β is synthetic lethal with fhit loss in lung cancer by blocking homologous recombination repair |
| url | https://doi.org/10.1038/s12276-024-01374-0 |
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