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ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis

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  • Ziqing Yang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Shaomin Zou

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Yijing Zhang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Jieping Zhang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Peng Zhang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Lishi Xiao

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Yunling Xie

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Manqi Meng

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Junyan Feng

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Liang Kang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Mong-Hong Lee

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

  • Lekun Fang

    (The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University
    The Sixth Affiliated Hospital, Sun Yat-sen University)

Abstract

Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.

Suggested Citation

  • Ziqing Yang & Shaomin Zou & Yijing Zhang & Jieping Zhang & Peng Zhang & Lishi Xiao & Yunling Xie & Manqi Meng & Junyan Feng & Liang Kang & Mong-Hong Lee & Lekun Fang, 2023. "ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39901-8
    DOI: 10.1038/s41467-023-39901-8
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    1. Sandipan Brahma & Mzwanele Ngubo & Somnath Paul & Maheshi Udugama & Blaine Bartholomew, 2018. "The Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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