The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer

Abstract

Although long noncoding RNAs (lncRNAs) predominately reside in nuclear and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identified a cytoplasmic lncRNA, Long-Intergenic Noncoding RNA for Kinase Activation (LINK-A), which mediates HB-EGF triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr565 and Ser797 by BRK and LRRK2 respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr565 phosphorylation interferes with Pro564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A and LINK-A-dependent signaling pathway activation correlate with TNBC, promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

“…In this study, GPNMB was associated with an HB-EGF-stimulated EGFR:GPNMB heterodimer complex [45]. Upon HB-EGF stimulation, EGFR phosphorylated the tyrosine residue in GPNMB’s hemITAM motif, leading to heterodimer formation and interaction with LINK-A (long intergenic non-coding RNA for kinase activation), a cytoplasmic long non-coding RNA (lncRNA).…”

“…Upon HB-EGF stimulation, EGFR phosphorylated the tyrosine residue in GPNMB’s hemITAM motif, leading to heterodimer formation and interaction with LINK-A (long intergenic non-coding RNA for kinase activation), a cytoplasmic long non-coding RNA (lncRNA). This complex formation then activated BRK (Breast tumor kinase), which mediated phosphorylation of hypoxia-inducible factor 1-alpha (HIF1α), allowing for its stabilization and upregulation of target genes, thereby promoting glycolysis reprogramming and tumorigenesis [45]. …”

JAK2-binding long noncoding RNA promotes breast cancer brain metastasis

“…269.7 nM of Lnc-BM reaches 50% maximal binding with JAK2, but not other lncRNAs that are highly expressed in breast cancer, including H19 (29) and LINK-A (ref. 26 and Figure 9E). Prediction of the secondary structure of Lnc-BM suggests that the 60-mer RNA fragment (nt 961-1,020) of Lnc-BM forms 3 stemloop structures (Supplemental Figure 8G).…”

Long non-coding RNA TRPM2-AS as a potential biomarker for hepatocellular carcinoma

“…Using high-throughput technologies, thousands of lncRNAs have recently been identified, and a large number of studies have demonstrated that dysregulated lncRNAs are closely related to human cancers [7], such as HCC [8], lung cancer [9], breast cancer [10], and colorectal cancer [7]. The expression levels of certain lncRNAs are associated with the recurrence [11], metastasis [12], and prognosis of cancers.…”