Abstract
LncRNAs have emerged as pivotal regulators in the development and progression of various human cancers. However, understanding the precise mechanisms by which lncRNAs influence cancer progression remains a substantial challenge, largely due to their cell type- and tissue-specific expression patterns and the lack of well-defined functional domains or motifs. In this study, we investigate the complex interplay between super-enhancers and lncRNAs through a comprehensive analysis of lncRNA expression in a cohort of metastatic castration-resistant prostate cancer patients. Our analysis identifies 1344 lncRNAs, among which an antisense lncRNA in the IGF1R locus named IGF1R-AS1 displayed the strongest super-enhancer association. Through pan-cancer transcriptome analysis, we find that IGF1R-AS1 is specifically transcribed in tumor specimens and is overexpressed in prostate and lung cancers. Notably, we reveal a non-canonical trans-acting role for IGF1R-AS1 whereby it interacts with chromatin remodeling complexes and architectural proteins to facilitate long-range chromatin looping between distal MYC enhancers and its promoter, leading to MYC overexpression and enhanced tumorigenicity. Collectively, our findings elucidate a mechanism by which a tumor-specific trans-acting lncRNA modulates oncogenic MYC expression through long-range chromatin interactions, suggesting IGF1R-AS1 may play an important role in the pathogenesis of MYC-driven malignancies.

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