2. Academic Validation
  3. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1

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

  • Nat Commun. 2018 Apr 30;9(1):1723. doi: 10.1038/s41467-018-04010-4.
Boyi Zhang 1,  Da Fu 2,  Qixia Xu 3,  Xianling Cong 4,  Chunyan Wu 5,  Xiaoming Zhong 6,  Yushui Ma 7,  Zhongwei Lv 7,  Fei Chen 1,  Liu Han 1,  Min Qian 1,  Y Eugene Chin 1,  Eric W-F Lam 8,  Paul Chiao 9,  Yu Sun 10 11
Affiliations

Affiliations

  • 1 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, 200031, Shanghai, China.
  • 2 Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China.
  • 3 Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  • 4 Tissue Bank, China-Japan Union Hospital, Jilin University, 130033, Changchun, Jilin, China.
  • 5 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433, Shanghai, China.
  • 6 Department of Radiology, Jiangxi Provincial Tumour Hospital/Ganzhou City People's Hospital, 330029, Nanchang, Jiangxi, China.
  • 7 Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072, Shanghai, China.
  • 8 Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
  • 9 Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 10 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, 200031, Shanghai, China. [email protected].
  • 11 Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, 98195, USA. [email protected].
PMID: 29712904 DOI: 10.1038/s41467-018-04010-4
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.

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