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Updated: Jun 7, 2025

Live Imaging of the Mitochondrial Glutathione Redox State in Primary Neurons using a Ratiometric Indicator
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SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling

Jiaguan Zhang1, Zeshou Gao2, Yi Yang1

  • 1Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.

Cell Death & Disease
|November 12, 2024
PubMed

Insights

SNF2L deficiency in cancer cells lowers glutathione (GSH), increasing oxidative stress and sensitivity to APR-246. Targeting the SNF2L/SLC7A11 pathway offers a new therapeutic strategy for cancer treatment.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Chromatin Remodeling

Background:

  • SNF2L, an ISWI chromatin remodeler, is upregulated in cancers and crucial for gene transcription.
  • Inhibiting SNF2L suppresses cancer cell growth, induces DNA damage, and causes cell death, but mechanisms are unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which SNF2L influences cancer cell viability and drug sensitivity.
  • To investigate the role of SNF2L in regulating glutathione (GSH) levels and oxidative stress.

Main Methods:

  • Assessed glutathione (GSH) and reactive oxygen species (ROS) levels in SNF2L-deficient cancer cells.
  • Evaluated cancer cell sensitivity to APR-246 treatment.
  • Investigated the SNF2L/SLC7A11 interaction at the promoter region using chromatin accessibility assays and transcription analysis.

Main Results:

  • SNF2L-deficient cells exhibited significantly reduced GSH levels, leading to increased ROS and oxidative stress.
  • SNF2L deficiency sensitized cancer cells to APR-246, decreasing viability and increasing ROS, irrespective of p53 status.
  • NRF2 recruits SNF2L to the SLC7A11 promoter, enhancing chromatin accessibility and SLC7A11 transcription, which impairs GSH biosynthesis.

Conclusions:

  • SNF2L plays a critical role in maintaining GSH levels and mitigating oxidative stress in cancer cells.
  • The SNF2L/SLC7A11 axis is a key regulator of GSH biosynthesis and influences cancer cell response to oxidative stress-inducing drugs.
  • Targeting the SNF2L/SLC7A11 pathway presents a potential therapeutic strategy to enhance APR-246 efficacy in cancer treatment.

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