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

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Title: The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1
Authors: Zhang, B
Fu, D
Xu, Q
Cong, X
Wu, C
Zhong, X
Ma, Y
Lv, Z
Chen, F
Han, L
Qian, M
Chin, YE
Lam, EW
Chiao, P
Sun, Y
Item Type: Journal Article
Abstract: The senescence-associated secretory phenotyp e (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 treat ment-induced damage remains unclear. Here we report that the transcription fa ctor 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 depri ves cancer cells of r esistance acquired from treatment-damag ed stromal cells in vitro and substantially promotes tumour regression in vivo . Together, our study reveals a novel network that links functionally critical molecules associ ated with the SASP development in therapeutic settings, thus opening new ave nues to improve clinical outcomes and advance precision medicine.
Issue Date: 30-Apr-2018
Date of Acceptance: 28-Mar-2018
URI: http://hdl.handle.net/10044/1/58663
DOI: https://dx.doi.org/10.1038/s41467-018-04010-4
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 30
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article ’ s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 1723
Appears in Collections:Department of Surgery and Cancer