XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis
- Authors
- Jeong, Seong-In; Kim, Jung-Wook; Ko, Kyung-Phil; Ryu, Byung-Kyu; Lee, Min-Goo; Kim, Hyo-Jong; Chi, Sung-Gil
- Issue Date
- 24-7월-2018
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- CELL DEATH & DISEASE, v.9
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL DEATH & DISEASE
- Volume
- 9
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/74313
- DOI
- 10.1038/s41419-018-0867-4
- ISSN
- 2041-4889
- Abstract
- 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 stressinduced 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-1mediated transcription of proapoptotic genes via the XAF1-IRF-1 complex formation on these target promoters. Meanwhile, XAF1 inhibits NF-.B-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 IRF1 under stressful conditions.
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