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

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.

Crosstalk between lncRNAs and Wnt/β-catenin signaling pathways in lung cancers: From cancer progression to therapeutic response

“…HIF1A-AS2, a KRAS responding lncRNA, was found to be elevated in LC and its high expression was correlated with poor patient prognosis. HIF-1A-AS2 and MYC formed a double-regulatory loop that could pro-mote cell survival, tumor growth and metastasis [ 108 ]. Increased levels of LINC00669 was generally linked with a bad prognosis.…”

The role of long non-coding RNA in Crohn's disease

“…HIF1A-AS2, also known as long intergenic non-protein coding RNA 2055 (LINC02055) or HOX transcript antisense RNA (HOTAIR), resides on chromosome 14q23.2 [ 46 ]. It is transcribed from the antisense strand of the HIF1A gene, encoding the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor.…”

New mechanism of LncRNA: In addition to act as a ceRNA

“…Further studies revealed that lncRNA HIF1A-AS2 could directly bind to DHX9 and recruit it to the MYC promoter to activate the transcription of MYC, while MYC was able to respond to the induction of KRAS and promote the expression of lncRNA HIF1A-AS2. LncRNA HIF1A-AS2 regulated and formed a double-feeding loop with MYC in both directions, which further enhanced the proliferation and tumor metastasis of lung cancer cells [ 43 ].

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