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XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis
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XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis
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Journal Article
XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis
2018
Overview
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a proapoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, the molecular basis for the XAF1-mediated growth inhibition remains largely undefined. Here, we report that XAF1 forms a positive feedback loop with interferon regulatory factor-1 (IRF-1) and functions as a transcriptional coactivator of IRF-1 to suppress tumorigenesis. Under various stressful conditions,
XAF1
transcription is activated by IRF-1, and elevated XAF1 stabilizes and activates IRF-1. Mechanistically, XAF1 binds to the multifunctional domain 2 of IRF-1 via the zinc finger domain 6, thereby hindering C-terminus of Hsc70-interacting protein (CHIP) interaction with and ubiquitination of IRF-1. Activation of the IRF-1−XAF1 loop greatly increases stress-induced apoptosis and decreases the invasive capability of tumor cells. Oncogenic Ras and growth factors interfere with the IRF-1−XAF1 interplay via Erk-mediated repression of
XAF1
transcription. Furthermore, XAF1 enhances IRF-1-mediated transcription of proapoptotic genes via the XAF1-IRF-1 complex formation on these target promoters. Meanwhile, XAF1 inhibits NF-κB-mediated tumor cell malignancy by reinforcing IRF-1 binding to a subset of coregulated promoters. Expression levels of IRF-1 and XAF1 correlate tightly in both cancer cell lines and primary tumors, and XAF1-induced tumor regression is markedly attenuated in IRF-1-depleted tumors. Collectively, this study identifies a novel mechanism of XAF1-mediated tumor suppression, uncovering XAF1 as a feedback coactivator of IRF-1 under stressful conditions.
Publisher
Nature Publishing Group UK,Springer Nature B.V
Subject
/ 38/109
/ 42
/ 96
/ 96/109
/ 96/2
/ 96/21
/ 96/31
/ 96/95
/ Biomedical and Life Sciences
/ Cancer
/ Feedback
/ Interferon regulatory factor
/ Interferon regulatory factor 1
/ Tumors
