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Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells

Author

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  • Chia-Lin Chen

    (Institute of Molecular and Genomic Medicine, National Health Research Institutes)

  • Sheng-Chieh Hsu

    (National Tsing-Hua University
    Institute of Cellular and System Medicine, National Health Research Institutes)

  • Tan-Ya Chung

    (Institute of Molecular and Genomic Medicine, National Health Research Institutes)

  • Cheng-Ying Chu

    (Taipei Medical University)

  • Hung-Jung Wang

    (Tzu Chi University)

  • Pei-Wen Hsiao

    (Academia Sinica)

  • Shauh-Der Yeh

    (Taipei Medical University Hospital
    Taipei Medical University)

  • David K. Ann

    (Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope)

  • Yun Yen

    (Taipei Medical University)

  • Hsing-Jien Kung

    (Institute of Molecular and Genomic Medicine, National Health Research Institutes
    Taipei Medical University
    Taipei Medical University
    University of California at Davis)

Abstract

Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.

Suggested Citation

  • Chia-Lin Chen & Sheng-Chieh Hsu & Tan-Ya Chung & Cheng-Ying Chu & Hung-Jung Wang & Pei-Wen Hsiao & Shauh-Der Yeh & David K. Ann & Yun Yen & Hsing-Jien Kung, 2021. "Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22652-9
    DOI: 10.1038/s41467-021-22652-9
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    Cited by:

    1. Chenglong Sun & Anqiang Wang & Yanhe Zhou & Panpan Chen & Xiangyi Wang & Jianpeng Huang & Jiamin Gao & Xiao Wang & Liebo Shu & Jiawei Lu & Wentao Dai & Zhaode Bu & Jiafu Ji & Jiuming He, 2023. "Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Yueli Yang & Wenqi Jia & Zhiwei Luo & Yunpan Li & Hao Liu & Lixin Fu & Jinxiu Li & Yu Jiang & Junjian Lai & Haiwei Li & Babangida Jabir Saeed & Yi Zou & Yuan Lv & Liang Wu & Ting Zhou & Yongli Shan & , 2024. "VGLL1 cooperates with TEAD4 to control human trophectoderm lineage specification," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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