NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair
Abstract Chemotherapeutic agents, including cisplatin, have remained a cornerstone of lung adenocarcinoma (LUAD) treatment and continue to play an essential role in clinical practice, despite remarkable progress in therapeutic strategies. Hence, a thorough comprehension of the molecular mechanisms u...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06256-3 |
| _version_ | 1797273056064831488 |
|---|---|
| author | Youyu Zhang Yuqiao Chen Wentao Huang Yuan Zhou Ya Wang Kai Fu Wei Zhuang |
| author_facet | Youyu Zhang Yuqiao Chen Wentao Huang Yuan Zhou Ya Wang Kai Fu Wei Zhuang |
| author_sort | Youyu Zhang |
| collection | DOAJ |
| description | Abstract Chemotherapeutic agents, including cisplatin, have remained a cornerstone of lung adenocarcinoma (LUAD) treatment and continue to play an essential role in clinical practice, despite remarkable progress in therapeutic strategies. Hence, a thorough comprehension of the molecular mechanisms underlying chemotherapeutic agent resistance is paramount. Our investigation centered on the potential involvement of the NPAS2 gene in LUAD, which is highly expressed in tumors and its high expression has been associated with unfavorable overall survival rates in patients. Intriguingly, we observed that the depletion of NPAS2 in LUAD cells resulted in increased susceptibility to cisplatin treatment. Furthermore, mRNA sequencing analysis revealed that NPAS2 deficiency downregulated genes crucial to DNA repair. Additionally, NPAS2 depletion significantly impairs γH2AX accumulation, a pivotal component of the DNA damage response. Further investigation demonstrates that NPAS2 plays a crucial role in DNA double-strand breakage repair via homology-directed repair (HDR). Our inquiry into the molecular mechanisms underlying NPAS2 regulation of DDR revealed that it may enhance the stability of H2AX mRNA by binding to its mRNA, thereby upregulating the DNA damage repair pathway. In-vivo experiments further confirmed the crucial role of NPAS2 in modulating the effect of cisplatin in LUAD. Taken together, our findings suggest that NPAS2 binds to and enhances the stability of H2AX mRNA, thereby decreasing the sensitivity of tumor cells to chemotherapy by augmenting DNA damage repair. |
| first_indexed | 2024-03-07T14:39:05Z |
| format | Article |
| id | doaj.art-b5aa84942f024487b095a0fa1452e8e1 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:39:05Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-b5aa84942f024487b095a0fa1452e8e12024-03-05T20:30:38ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111210.1038/s41419-023-06256-3NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repairYouyu Zhang0Yuqiao Chen1Wentao Huang2Yuan Zhou3Ya Wang4Kai Fu5Wei Zhuang6Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South UniversityInstitute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South UniversityDepartment of Thoracic Surgery, Xiangya Hospital, Central South UniversityDepartment of Thoracic Surgery, Xiangya Hospital, Central South UniversityInstitute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South UniversityInstitute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South UniversityDepartment of Thoracic Surgery, Xiangya Hospital, Central South UniversityAbstract Chemotherapeutic agents, including cisplatin, have remained a cornerstone of lung adenocarcinoma (LUAD) treatment and continue to play an essential role in clinical practice, despite remarkable progress in therapeutic strategies. Hence, a thorough comprehension of the molecular mechanisms underlying chemotherapeutic agent resistance is paramount. Our investigation centered on the potential involvement of the NPAS2 gene in LUAD, which is highly expressed in tumors and its high expression has been associated with unfavorable overall survival rates in patients. Intriguingly, we observed that the depletion of NPAS2 in LUAD cells resulted in increased susceptibility to cisplatin treatment. Furthermore, mRNA sequencing analysis revealed that NPAS2 deficiency downregulated genes crucial to DNA repair. Additionally, NPAS2 depletion significantly impairs γH2AX accumulation, a pivotal component of the DNA damage response. Further investigation demonstrates that NPAS2 plays a crucial role in DNA double-strand breakage repair via homology-directed repair (HDR). Our inquiry into the molecular mechanisms underlying NPAS2 regulation of DDR revealed that it may enhance the stability of H2AX mRNA by binding to its mRNA, thereby upregulating the DNA damage repair pathway. In-vivo experiments further confirmed the crucial role of NPAS2 in modulating the effect of cisplatin in LUAD. Taken together, our findings suggest that NPAS2 binds to and enhances the stability of H2AX mRNA, thereby decreasing the sensitivity of tumor cells to chemotherapy by augmenting DNA damage repair.https://doi.org/10.1038/s41419-023-06256-3 |
| spellingShingle | Youyu Zhang Yuqiao Chen Wentao Huang Yuan Zhou Ya Wang Kai Fu Wei Zhuang NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair Cell Death and Disease |
| title | NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair |
| title_full | NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair |
| title_fullStr | NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair |
| title_full_unstemmed | NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair |
| title_short | NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair |
| title_sort | npas2 dampens chemo sensitivity of lung adenocarcinoma cells by enhancing dna damage repair |
| url | https://doi.org/10.1038/s41419-023-06256-3 |
| work_keys_str_mv | AT youyuzhang npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT yuqiaochen npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT wentaohuang npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT yuanzhou npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT yawang npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT kaifu npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair AT weizhuang npas2dampenschemosensitivityoflungadenocarcinomacellsbyenhancingdnadamagerepair |