XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis

Seong In Jeong, Jung Wook Kim, Kyung Phil Ko, Byung Kyu Ryu, Min Goo Lee, Hyo Jong Kim, Sung Gil Chi

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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.

Original languageEnglish
Article number806
JournalCell Death and Disease
Issue number8
Publication statusPublished - 2018 Aug 1

Bibliographical note

Funding Information:
The authors thank Dr. S.-J. Um (Sejong University, Seoul, Korea) for HA-tagged human IRF-1 expression vector, Dr. J.-H. Kim (Korea University, Seoul, Korea) for pGL3-MMP9-Luc reporter plasmid. This work was supported in part by grants to S.-G.C. (NRF-2015R1A2A1A01005389) and M.-G.L. (NRF- 2015R1D1A4A01016836) from National Research Foundation of Korea and a Korea University Intramural Grant-in-Aid (2017).

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


Dive into the research topics of 'XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis'. Together they form a unique fingerprint.

Cite this