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辐射诱导的 YAP/TEAD4 结合通过促进 NRP1 转录赋予非小细胞肺癌放射抵抗性。

Radiation-induced YAP/TEAD4 binding confers non-small cell lung cancer radioresistance via promoting NRP1 transcription.

机构信息

NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, Jilin, China.

Department of Orthopedics, The First Hospital of Jilin University, Changchun, Jilin, China.

出版信息

Cell Death Dis. 2024 Aug 26;15(8):619. doi: 10.1038/s41419-024-07017-6.

DOI:10.1038/s41419-024-07017-6
PMID:39187525
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11347582/
Abstract

Despite the importance of radiation therapy as a non-surgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern, due to poor patient response and prognosis. Therefore, it is crucial to uncover novel targets to enhance radiotherapy and investigate the mechanisms underlying radiation resistance. Previously, we demonstrated that NRP1 was connected to radiation resistance in NSCLC cells. In the present study, bioinformatics analysis of constructed radiation-resistant A549 and H1299 cell models revealed that transcription coactivator YAP is a significant factor in cell proliferation and metastasis. However, there has been no evidence linking YAP and NRP1 to date. In this research, we have observed that YAP contributes to radiation resistance in NSCLC cells by stimulating cell proliferation, migration, and invasion. Mechanistically, YAP dephosphorylation after NSCLC cell radiation. YAP acts as a transcription co-activator by binding to the transcription factor TEAD4, facilitating TEAD4 to bind to the NRP1 promoter region and thereby increasing NRP1 expression. NRP1 has been identified as a new target gene for YAP/TEAD4. Notably, when inhibiting YAP binds to TEAD4, it inhibits NRP1 expression, and Rescue experiments show that YAP/TEAD4 influences NRP1 to regulate cell proliferation, metastasis and leading to radiation resistance generation. According to these results, YAP/TEAD4/NRP1 is a significant mechanism for radioresistance and can be utilized as a target for enhancing radiotherapy efficacy.

摘要

尽管放射疗法作为非小细胞肺癌（NSCLC）的非手术治疗方法非常重要，但由于患者反应和预后不佳，放射抵抗一直是一个令人关注的问题。因此，揭示新的靶点以增强放射治疗并研究放射抵抗的机制至关重要。先前，我们已经证明了 NRP1 与 NSCLC 细胞的放射抵抗有关。在本研究中，构建的放射抵抗 A549 和 H1299 细胞模型的生物信息学分析表明，转录共激活因子 YAP 是细胞增殖和转移的重要因素。然而，目前尚无证据将 YAP 和 NRP1 联系起来。在这项研究中，我们观察到 YAP 通过刺激细胞增殖、迁移和侵袭来促进 NSCLC 细胞的放射抵抗。从机制上讲，YAP 在 NSCLC 细胞受到辐射后发生去磷酸化。YAP 通过与转录因子 TEAD4 结合作为转录共激活因子，促进 TEAD4 结合到 NRP1 启动子区域，从而增加 NRP1 的表达。NRP1 已被确定为 YAP/TEAD4 的新靶基因。值得注意的是，当抑制 YAP 与 TEAD4 结合时，它会抑制 NRP1 的表达，并且挽救实验表明 YAP/TEAD4 影响 NRP1 来调节细胞增殖、转移并导致放射抵抗的产生。根据这些结果，YAP/TEAD4/NRP1 是放射抵抗的重要机制，可以作为增强放射治疗效果的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/65bcdc8ab950/41419_2024_7017_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/c5a2a06753ac/41419_2024_7017_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/884748087864/41419_2024_7017_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/bde6b21688b3/41419_2024_7017_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/e3c71fb855ce/41419_2024_7017_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/46c598674a1c/41419_2024_7017_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/9454b2cccc66/41419_2024_7017_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/68440e8fced9/41419_2024_7017_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/65bcdc8ab950/41419_2024_7017_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/c5a2a06753ac/41419_2024_7017_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/884748087864/41419_2024_7017_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/bde6b21688b3/41419_2024_7017_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/e3c71fb855ce/41419_2024_7017_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/46c598674a1c/41419_2024_7017_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/9454b2cccc66/41419_2024_7017_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/68440e8fced9/41419_2024_7017_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3fd/11347582/65bcdc8ab950/41419_2024_7017_Fig8_HTML.jpg

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