Copy number amplification and SP1-activated lncRNA MELTF-AS1 regulates tumorigenesis by driving phase separation of YBX1 to activate ANXA8 in non-small cell lung cancer

• Published in: Oncogene 2022-06, Vol.41 (23), p.3222-3238
• Main Authors: Lu, Xiyi, Wang, Jing, Wang, Wei, Lu, Chenfei, Qu, Tianyu, He, Xuezhi, Liu, Xinyin, Guo, Renhua, Zhang, Erbao
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/89; 45/90; 631/337/384; 692/53; 82; Apoptosis; Carcinogenesis - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Copy number; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Gene regulation; Genomes; Human Genetics; Humans; Internal Medicine; Lung cancer; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Non-coding RNA; Non-small cell lung carcinoma; Oncology; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-binding protein; Sequence analysis; Small cell lung carcinoma; Sp1 protein; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Therapeutic targets; Tumorigenesis; Y-Box-Binding Protein 1 - genetics; Y-Box-Binding Protein 1 - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02292-z

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.