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<p>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 <i>IGF1R</i> locus named <i>IGF1R-AS1</i> displayed the strongest super-enhancer association. Through pan-cancer transcriptome analysis, we find that <i>IGF1R-AS1</i> is specifically transcribed in tumor specimens and is overexpressed in prostate and lung cancers. Notably, we reveal a non-canonical <i>trans</i>-acting role for <i>IGF1R-AS1</i> whereby it interacts with chromatin remodeling complexes and architectural proteins to facilitate long-range chromatin looping between distal <i>MYC</i> enhancers and its promoter, leading to <i>MYC</i> overexpression and enhanced tumorigenicity. Collectively, our findings elucidate a mechanism by which a tumor-specific <i>trans</i>-acting lncRNA modulates oncogenic <i>MYC</i> expression through long-range chromatin interactions, suggesting <i>IGF1R-AS1</i> may play an important role in the pathogenesis of MYC-driven malignancies.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • 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

摘要

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.