Scholarlink

<p>Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key regulator of cell detoxification, which maintains homoeostasis in healthy cells and promotes chemoresistance in cancer cells. Controlling the expression of this transcription factor is therefore of great interest. There are many compounds that have been shown to induce <i>Nrf2</i> expression, but ligands that can inhibit Nrf2 are scant. Herein we characterise an i-motif-forming sequence downstream of the <i>Nrf2</i> promoter, which we hypothesised may regulate the expression of the gene. The Nrf2 i-motif was found to be stable at near-physiological conditions. We identified small molecule ligands that interact with this i-motif structure and one significantly upregulated Nrf2 mRNA expression, and one ligand reduced Nrf2 mRNA expression in human cancer cells. This is the first example of controlling the promoter of <i>Nrf2</i> by targeting DNA structures and offers an alternative mode of action for the development of compounds to improve the chemotherapeutic responsiveness of existing treatments for cancer.</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

Modulation of Nrf2 expression by targeting i-motif DNA

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月6日

查看全文
  • E. F. Warner,
  • D. Guneri,
  • M. A. O’Connell,
  • C. J. MacDonald,
  • Z. A. E. Waller

摘要

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key regulator of cell detoxification, which maintains homoeostasis in healthy cells and promotes chemoresistance in cancer cells. Controlling the expression of this transcription factor is therefore of great interest. There are many compounds that have been shown to induce Nrf2 expression, but ligands that can inhibit Nrf2 are scant. Herein we characterise an i-motif-forming sequence downstream of the Nrf2 promoter, which we hypothesised may regulate the expression of the gene. The Nrf2 i-motif was found to be stable at near-physiological conditions. We identified small molecule ligands that interact with this i-motif structure and one significantly upregulated Nrf2 mRNA expression, and one ligand reduced Nrf2 mRNA expression in human cancer cells. This is the first example of controlling the promoter of Nrf2 by targeting DNA structures and offers an alternative mode of action for the development of compounds to improve the chemotherapeutic responsiveness of existing treatments for cancer.