Identification of transcriptome-wide cobalt chloride-induced hypoxia-responsive long noncoding RNAs regulated by cytoplasmic mRNA capping enzyme

Abstract

Long non-coding RNAs (lncRNAs) are key regulators of gene expression in human cancers, influencing tumor microenvironment (TME). Hypoxia, a hallmark of solid tumors, elevates hypoxia-inducible factor 1 (HIF-1), which regulates hypoxia-responsive lncRNAs (HRLs). These HRLs are essential in regulating gene expression under hypoxic conditions at both transcriptional and post-transcriptional levels. However, the mechanisms governing the post-transcriptional regulation of lncRNAs are not fully understood. It has been shown that the cytoplasmic pool of mRNA capping enzyme (cCE) can post-transcriptionally regulate its substrate uncapped mRNAs and lncRNAs in the cytoplasm, thereby preventing their degradation. Our previous study showed elevated expression of cCE under hypoxic conditions. This study aimed to determine whether cCE influences the transcriptome-wide HRLs in CoCl2-induced hypoxia in osteosarcoma U2OS cells. We identified 306 known lncRNAs with significant differential expression under hypoxic conditions, including 137 upregulated and 169 downregulated by RNA sequencing. Gene Ontology enrichment analysis revealed their distinct association with various cancers. Our investigation aimed to ascertain whether the cCE post-transcriptionally regulates these HRLs. Overexpression of a dominant negative form of cCE suggested cCE might post-transcriptionally regulate these HRLs. Future research should focus on understanding how cCE influences substrate HRLs, which play a crucial role in the bidirectional signaling circuit between TME and cancer cells under hypoxic stress as well as establishing cCE as a key factor that may alter cellular responses to hypoxia by stabilizing cCE-targeted lncRNAs.