Scholarlink

<p>Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers (NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in cancer cell lines, and observed that a significant portion of these genes is devoid of promoter-proximal NRF2 occupancy. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent cancer cell growth does not require this enhanced glutathione production.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月14日

查看全文
  • Ryan J Conrad,
  • James A Mondo,
  • Mike Lingjue Wang,
  • Peter S Liu,
  • Zijuan Lai,
  • Feroza K Choudhury,
  • Qingling Li,
  • Weng Ruh Wong,
  • James Lee,
  • Frances Shanahan,
  • Eva Lin,
  • Scott Martin,
  • Joachim Rudolph,
  • John G Moffat,
  • Dewakar Sangaraju,
  • Wendy Sandoval,
  • Timothy Sterne-Weiler,
  • Scott A Foster

摘要

Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers (NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in cancer cell lines, and observed that a significant portion of these genes is devoid of promoter-proximal NRF2 occupancy. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent cancer cell growth does not require this enhanced glutathione production.