期刊
ONCOGENE
卷 41, 期 23, 页码 3222-3238出版社
SPRINGERNATURE
DOI: 10.1038/s41388-022-02292-z
关键词
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资金
- National Natural Science Foundation of China [82172992, 81972188, 82103133]
- Natural Science Foundation of Jiangsu Province [BK20211253, BK20210973]
- China Postdoctoral Science Foundation [2020M671395]
- Medical Important Talents [ZDRCA2016024]
- Program for Innovative Research Team of Nanjing Medical University [JX102GSP201727]
- Wu Jie-ping Foundation [320.6799.15032]
This study identified an oncogenic long non-coding RNA (lncRNA) called MELTF-AS1 that is significantly upregulated in non-small cell lung cancer (NSCLC). MELTF-AS1 was found to regulate cell proliferation and metastasis, and its knockdown specifically modulated genes associated with cell proliferation, apoptosis, and migration. Furthermore, MELTF-AS1 was shown to directly bind and drive the phase separation of YBX1, an RNA-binding protein involved in tumorigenesis, leading to the activation of ANXA8 transcription and promotion of NSCLC tumorigenesis.
Long non-coding RNAs (lncRNAs) are reported to play key roles in tumorigenesis. However, the mechanisms underlying lncRNA-mediated regulation of RNA-binding protein phase separation in tumorigenesis have not been completely elucidated. In this study, an oncogenic lncRNA MELTF-AS1 was identified using systematic data analysis, screening, and verification. MELTF-AS1 was markedly upregulated in non-small cell lung cancer (NSCLC). High MELTF-AS1 levels were associated with advanced tumor-node-metastasis stage (TNM), high tumor size, and decreased survival time. Functionally, MELTF-AS1 regulated cell proliferation and metastasis in vitro and in vivo. RNA sequencing analysis revealed that MELTF-AS1 knockdown specifically modulated genes associated with cell proliferation, apoptosis, and migration. Mechanistically, at the genome level, copy number amplification promoted MELTF-AS1 expression. At the transcriptional level, the transcription factor SP1 directly activated MELTF-AS1 transcription by binding to its promoter. Furthermore, MELTF-AS1 could directly bind and drive the phase separation of YBX1, which was an RNA-binding protein and involved in tumorigenesis, thus activating ANXA8 transcription and promoting tumorigenesis of NSCLC. Aberrant activation of ANXA8 and promotion of tumorigenesis have been found in a variety of tumors. These novel findings demonstrated the critical role of MELTF-AS1-driven phase separation-mediated transcriptional regulation and provided a potential novel diagnostic and therapeutic target for NSCLC.
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