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FAK-LINC01089 negative regulatory loop controls chemoresistance and progression of small cell lung cancer

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机构： [1]Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen 518060, China. [2]Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [3]Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China. [4]School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China. [5]Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [6]State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. [7]Chongqing Key Laboratory of Sichuan-Chongging Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China. [8]Graduate School, Guangxi University of Chinese Medicine, Nanning, China.

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The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

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大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区遗传学 2 区细胞生物学 2 区肿瘤学

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Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY Q1 GENETICS & HEREDITY Q1 ONCOLOGY

影响因子： 6.9 最新[2023版] 7.5 最新五年平均 6.9 出版当年[2023版] 0 出版当年五年平均 6.9 出版前一年[2023版]

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第一作者机构： [1]Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen 518060, China. [2]Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [3]Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China. [4]School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China.

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通讯作者：

通讯机构： [1]Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen 518060, China. [2]Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [3]Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

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