The MYC-induced Long Non-Coding RNA MINCR as a potential novel player in cell cycle regulation in prostate cancer

Amplifications of chromosome 8q24 are found in various diseases, including prostate cancer, especially in cases of severe disease. Although this region, named "gene desert," contains few protein-coding genes, with c-MYC being one of the notable oncogenes within it, it is rich in long non-coding RNAs, some of which are linked to c-MYC expression. Among them, MINCR (MYC-induced Long Non-Coding RNA) has emerged as a significant player in different cancers and also in non-tumor-related diseases such as osteoarthritis and amyotrophic lateral sclerosis. Given the lack of information regarding the relevance of MINCR and 8q24 amplification in prostate cancer, this study aims to investigate the specific role of MINCR in the disease. By identifying patients where only MINCR chromosomal subregion is amplified without concurrent amplification of c-MYC, or patients with increased MINCR expression and no overexpression of c-MYC, we confirmed MINCR upregulation in prostate cancer cell lines and tissues compared to normal counterparts, particularly in metastatic or severe disease cases. Bona fide MINCR isoforms were reannotated by analyzing long-read sequencing data. Overall, we found that MINCR has a preferentially cytosolic localization in prostate cell lines. Analysis of publicly available datasets demonstrated a positive correlation between MINCR expression and cell cycle-related genes, including c-MYC targets. ASO-mediated loss of function studies revealed that silencing of MINCR by independent gapmer ASOs targeting all the isoforms led to decreased cell proliferation. RNA-sequencing on MINCR-knocked down cells identified pathways related to cell cycle regulation and mitotic spindle formation among down-regulated genes and inflammatory response and cholesterol homeostasis in up-regulated ones. Briefly, MINCR is overexpressed in prostate cancer and correlates with disease severity. It exhibits pro-proliferative and oncogenic activities, and its silencing results in downregulation of cell cycle-promoting genes, highlighting its potential as a therapeutic target, especially for cases resistant to traditional treatments. Further investigations into the activities of the single isoforms, the relationship between MINCR and the c-MYC pathway, and its additional cellular functions, are warranted.