The gene encoding for MINCR (MYC induced long non-coding RNA) is located on chromosome 8, 15 Mb telomeric to MYC. While the two genes are often coamplified, we identified a substantial proportion of patients with advanced prostate cancer where MINCR is amplified independently of MYC, implying a distinct oncogenic potential for MINCR. While MINCR has emerged as a significant player in many cancers, no efforts have been made to elucidate its impact on prostate cancer progression and the specific role of MINCR isoforms remains unexplored.

MINCR transcript characterization was performed through in silico analyses using publicly available cancer datasets and annotation databases. MINCR silencing was obtained using either blocking or degrading antisense oligonucleotides. For overexpression, isoform-specific sequences were cloned in plasmids. RNA sequencing followed by gene set enrichment analysis (GSEA) was used to provide mechanistic hints on how MINCR impacts prostate cancer tumorigenesis. Quantitative PCR analysis and in vitro cellular assays were performed to validate GSEA results.

We found that MINCR expression levels positively correlate with tumor grade and negatively with disease-free survival, highlighting that MINCR is highly expressed in more aggressive and advanced cases of prostate cancer. The analysis of PolyA site database, FANTOM CAGE data, and long-read sequencing data revealed the existence of two main isoforms, that we named short and long, localizing in the cytoplasm and in the nucleus, respectively. Modulation of MINCR short in prostate cancer cells resulted in more profound changes in gene expression, as compared to MINCR long. Overall, silencing of both isoforms impacted on cell growth, with cell cycle related genes (specifically M phase) being downregulated. MINCR involvement in cell proliferation was further confirmed in vitro; indeed, knocked-down DU145 and PC3 prostate cancer cells both showed decreased proliferation, whereas stably overexpressing clones displayed variably increased growth. Moreover, manipulation of both isoforms induced alterations of genes involved in androgen response, immunogenicity and NOTCH-pathway, features typically observed in neuroendocrine, aggressive prostate cancers. On the other hand, metabolism-related pathways, like glycolysis, resulted altered only when the short isoform was overexpressed, while genes involved in cell migration, cytoskeleton and extracellular matrix appeared selectively governed by MINCR long.

Our study reveals that MINCR isoforms exhibit distinct behaviors, yet both play crucial roles in driving prostate cancer progression and enhancing its aggressiveness. Investigating how MINCR influences cancer hallmarks and resistance to treatment could pave the way for novel targeted RNA-based therapeutic strategies.