Journal Article

Tumor-specific lncRNA IGF1R-AS1 trans-regulates chromatin interactions associated with oncogenic MYC signaling

Alam, Sk Kayum, Wang, Ting-You, Zhang, Xihong, White, Kyle H., Li, Yingming, Patchen, Nathan E., Meng, Qingshu, Weiner, Adam B., Ramakrishnan, Abhirami, Zhang, Xiaoyang, Zhang, Xingxing, Hoeppner, Luke H., Guo, Qingxiang, Fragkogianni, Stamatina, Cao, Qi, Yee, Douglas, Yang, Rendong, Irvin, Parker, Liu, Yang, Ren, Yanan, Ali, Taufeeque, Dawes, Courtney, Fry, Joshua, Yang, Yongyong, Schaeffer, Edward M., Li, Qianru, Dehm, Scott M.

2026

Overview

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. The role of long non-coding RNAs (lncRNAs) in regulating cancer progression remains to be explored. Here, the authors identify an antisense lncRNA in the IGF1R locus (IGF1RAS1) which strongly interacts with super enhancers and modulates MYC expression in metastatic prostate cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/15 / 38/39 / 38/91 / 631/114/2114 / 631/208/200 / 631/67/589/466 / 631/67/69 / Animals / Annotations / Carcinogenesis - genetics / Castration / Cell Line, Tumor / Chromatin - genetics / Chromatin - metabolism / Chromatin Assembly and Disassembly / Chromatin remodeling / Gene expression / Gene Expression Regulation, Neoplastic / Gene loci / Genomes / Humanities and Social Sciences / Humans / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Malignancy / Metastases / Metastasis / Mice / multidisciplinary / Myc protein / Non-coding RNA / Pathogenesis / Promoter Regions, Genetic / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Receptor, IGF Type 1 - genetics / Receptors, Somatomedin - genetics / Receptors, Somatomedin - metabolism / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Science / Science (multidisciplinary) / Signal Transduction - genetics / Super Enhancers / Transcriptomes / Tumorigenicity / Tumors