2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.02B.05 XBP1s-Related Super-Enhancers Suppresses Cuproptosis via Temporally Transcription Regulation in Lung Adenocarcinoma

EP.02B.05 XBP1s-Related Super-Enhancers Suppresses Cuproptosis via Temporally Transcription Regulation in Lung Adenocarcinoma

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This study by GU Yan and Wang Jun from the Department of Thoracic Surgery, Jiangsu Province Hospital, explores the role of endoplasmic reticulum (ER) stress-related super-enhancers in suppressing cuproptosis in lung adenocarcinoma (LUAD) through glycolysis reprogramming. The team investigates how these super-enhancers, particularly involving the molecule XBP1s, influence the pathology of LUAD when under copper stress.<br /><br />Copper, known to play a dual role in tumor biology, can induce cell death through cuproptosis. This research highlights how XBP1s, a stress-related factor, mitigates the effects of copper-induced cell death in LUAD cells by forming super-enhancers within the nucleus. These super-enhancers promote the transcription of target genes like MGRN1, enhancing glycolysis pathways and interacting with proteins involved in ubiquitination, such as LIPT1.<br /><br />Using methodologies like chromosome capture, CUT&Tag, and single-cell sequencing, the study shows that XBP1s forms nuclear condensates that compartmentalize coactivators to regulate gene expression. The study also reveals that under copper stress, the interaction between MGRN1 and distal enhancers is intensified, an effect that persists with the help of XBP1s condensates.<br /><br />The inhibition of cuproptosis via glycolysis reprogramming in the presence of LIPT1 deficiency suggests a cellular survival mechanism is at play. Furthermore, the study suggests the potential therapeutic benefit of combining super-enhancer inhibitors with existing treatments to suppress tumor growth in LUAD, demonstrated in xenograft models.<br /><br />Overall, the research identifies XBP1s as a crucial factor in tumor progression and resistance to copper-induced cell death, positioning it as a potential biomarker and therapeutic target for lung adenocarcinoma. The work was supported by the National Science Foundation of China, acknowledging contributions from collaborators and funding grants.

Asset Subtitle

Yan Gu

Meta Tag

Speaker Yan Gu

Topic Tumor Biology – Preclinical Biology

Keywords

endoplasmic reticulum stress

super-enhancers

cuproptosis

lung adenocarcinoma

glycolysis reprogramming

XBP1s

copper stress

MGRN1

LIPT1

therapeutic target