MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Abstract

Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.MYC | lncRNA | cell cycle | B-cell lymphoma M YC is a transcription factor belonging to the basic helixloop-helix zipper family that was originally identified in Burkitt lymphoma (BL) because of a chromosomal translocation that juxtaposes the MYC oncogene with one of three immunoglobulin (Ig) loci (1-3). In BL, the deregulation of the oncogenic transcription factor MYC is considered to be the major driving force in lymphoma development (4, 5). MYC overexpression is not restricted to BL and has been found to be a common feature SignificanceGains of the MYC gene are the most common imbalances in cancer and are associated with poor prognosis, particularly in B-cell lymphoma. Recent advances in DNA sequencing have revealed the existence of thousands of long noncoding RNAs (lncRNAs) with unknown functional relevance. We have here identified a MYC-regulated lncRNA that we named MYC-induced long noncoding RNA (MINCR) that has a strong correlation with MYC expression in cancer. We show that MINCR is functional and controls cell cycle progression by influencing the expression of MYC-regulated cell cycle genes. MINCR is, therefore, a novel player in MYC's transcriptional network, with the potential to open new therapeutic windows in the fight against malignant lymphoma and, possibly, all cancers that rely on MYC expression.

Long non-coding RNA MINCR promotes gallbladder cancer progression through stimulating EZH2 expression

“…1F). The role of MINCR in Burkitt lymphoma cells has been studied by others research team [13]. Whether MINCR was regulated by c-myc in GBC cells has never been reported before.…”

“…Thus, with the advancement of new technology, further studies about the relation between MYC and LncRNAs are being carry out [11,12]. MYC-induced long non-coding RNA (MINCR) is a newly defined LncRNA that is reported to be correlated with MYC expression in MYC-positive lymphomas [13]. To our knowledge, there is no published literature about MINCR in other cancers.…”

Noncoding RNAs Regulating p53 and c-Myc Signaling

“…Myc-induced long noncoding RNA (MINCR) has been recently identifi ed as a c-Myc-inducible lncRNA [ 98 ]. MINCR has a strong correlation with c-Myc expression in cancer.…”

The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation

“…Since c-Myc is upregulated in many human cancers it is subject to intense investigation for cancer treatment [15, 16]. Several studies have shown that c-Myc regulates the expression of long ncRNAs, and that some of these transcripts can participate in the transcriptional functions mediated by c-Myc [19-22]. Long ncRNA-mediated regulation of translation of c-Myc has also been suggested [23, 24].…”