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    Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer

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    Authors
    Yang, K.
    Zhang, W.
    Zhong, L.
    Xiao, Y.
    Sahoo, Sudhakar
    Fassan, M.
    Zeng, Kang
    Magee, Peter
    Garofalo, Michela
    Shi, Lei
    Affiliation
    RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China
    Issue Date
    2023
    
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    Abstract
    Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.
    Citation
    Yang K, Zhang W, Zhong L, Xiao Y, Sahoo S, Fassan M, et al. Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer. Cell death and differentiation. 2023 Apr 11:1-17. PubMed PMID: 37041291. Pubmed Central PMCID: PMC10089381. Epub 2023/04/12. eng.
    Journal
    Cell Death & Differentiation
    URI
    http://hdl.handle.net/10541/626222
    DOI
    10.1038/s41418-023-01160-x
    PubMed ID
    37041291
    Additional Links
    https://dx.doi.org/10.1038/s41418-023-01160-x
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41418-023-01160-x
    Scopus Count
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    All Paterson Institute for Cancer Research

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