Tumor-specific lncRNA IGF1R-AS1 trans-regulates chromatin interactions associated with oncogenic MYC signaling
- Yongyong Yang
- Ting-You Wang
- Joshua Fry
- Yingming Li
- Qingshu Meng
- Qingxiang Guo
- Nathan E. Patchen
- Kyle H. White
- Abhirami Ramakrishnan
- Yanan Ren
- Qianru Li
- Xingxing Zhang
- Taufeeque Ali
- Courtney Dawes
- Stamatina Fragkogianni
- Parker Irvin
- Sk Kayum Alam
- Luke H. Hoeppner
- Xihong Zhang
- Douglas Yee
- Adam B. Weiner
- Edward M. Schaeffer
- Yang Liu
- Xiaoyang Zhang
- Scott M. Dehm
- Qi Cao
- Rendong Yang
2026-03-19
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.