Loading...
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
Yang, K. Zhang, W. Zhong, L. Xiao, Y. Sahoo, Sudhakar Fassan, M. Zeng, Kang Magee, Peter Garofalo, Michela Shi, Lei
Yang, K.
Zhang, W.
Zhong, L.
Xiao, Y.
Sahoo, Sudhakar
Fassan, M.
Zeng, Kang
Magee, Peter
Garofalo, Michela
Shi, Lei
Citations
Altmetric:
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.
Description
Date
2023
Publisher
Collections
Files
Keywords
Type
Article
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.