RAIN Is a Novel Enhancer-Associated lncRNA That Controls RUNX2 Expression and Promotes Breast and Thyroid Cancer

Abstract

Enhancer (ENH)-associated long noncoding RNAs (lncRNA) are a peculiar class of RNAs produced by transcriptionally active ENHs, owning potential gene-regulatory function. Here, we characterized RAIN, a novel ENH-associated lncRNA. Analysis of RAIN expression in a retrospective cohort of human thyroid cancers showed that the expression of this lncRNA is restricted to cancer cells and strongly correlates with the expression of the cancer-promoting transcription factor RUNX2. We showed that RAIN, serving as a cisregulatory element, promotes RUNX2 expression by two mechanisms. Binding WDR5 and facilitating its localization on the RUNX2 promoter, RAIN modifies the transcriptional status of the RUNX2 locus facilitating transcription initiation. In parallel, RAIN acts as decoy for negative elongation factor complex, restraining its inhibitory function on transcription elongation. In both thyroid and breast cancer cells, RAIN promotes oncogenic features. Using RNAsequencing profiling, we showed that RAIN orchestrates the expression of a network of cancer-promoting transcription regulators, suggesting that RAIN affects cancer cell phenotype by coordinating the expression of a complex transcriptional network.Implications: Our data contribute to understand lncRNA function in gene regulation and to consolidate their role in cancer.

Comprehensive biological function analysis of lncRNAs in hepatocellular carcinoma

“…In the initial stage of lncRNA research, some scholars suggested that there is a difference in the expression of lncRNAs between tumor tissues and adjacent normal tissues. An increasing number of studies 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 have shown that lncRNAs may play an important biological role in the regulation of cancer development, as the biological function of lncRNAs in carcinomas is to promote cancer cell proliferation and invasion, suppress cancer cell proliferation and invasion, estimate the prognosis and efficacy, and act as potential biomarkers, as summarized in Table 1 .…”

Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

“…Non-coding RNAs are emerging as new key players in genomic function organization [76]. Micro RNAs (miRNAs) are short RNA molecules 18-25 nucleotides in length.…”

Regulation of RUNX proteins by long non-coding RNAs and circular RNAs in different cancers

“…WDR5 is a fundamental member of the histone H3K4 methyltransferase complexes ( Rossi , [ 46 ]). WDR5 promoted H3K4 trimethylation on active promoters and facilitated the recruitment of RNA-Pol-II for transcriptional activation of target genes.…”

“…RAIN restrained the NELFe-induced inhibitory effects on RUNX2 expression. There was a significant upregulation of RUNX2 in NELFe-silenced MDA-MB-231 and TPC1 cancer cells ( Rossi , [ 46 ]).…”