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The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1

Author

Listed:
  • Boyi Zhang

    (University of Chinese Academy of Sciences)

  • Da Fu

    (Tongji University School of Medicine)

  • Qixia Xu

    (Chinese Academy of Sciences)

  • Xianling Cong

    (Jilin University)

  • Chunyan Wu

    (Tongji University School of Medicine)

  • Xiaoming Zhong

    (Jiangxi Provincial Tumour Hospital/Ganzhou City People’s Hospital)

  • Yushui Ma

    (Shanghai Tenth People’s Hospital, Tongji University School of Medicine)

  • Zhongwei Lv

    (Shanghai Tenth People’s Hospital, Tongji University School of Medicine)

  • Fei Chen

    (University of Chinese Academy of Sciences)

  • Liu Han

    (University of Chinese Academy of Sciences)

  • Min Qian

    (University of Chinese Academy of Sciences)

  • Y. Eugene Chin

    (University of Chinese Academy of Sciences)

  • Eric W. -F. Lam

    (Imperial College London)

  • Paul Chiao

    (The University of Texas, MD Anderson Cancer Center)

  • Yu Sun

    (University of Chinese Academy of Sciences
    University of Washington)

Abstract

The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.

Suggested Citation

  • Boyi Zhang & Da Fu & Qixia Xu & Xianling Cong & Chunyan Wu & Xiaoming Zhong & Yushui Ma & Zhongwei Lv & Fei Chen & Liu Han & Min Qian & Y. Eugene Chin & Eric W. -F. Lam & Paul Chiao & Yu Sun, 2018. "The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04010-4
    DOI: 10.1038/s41467-018-04010-4
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