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

• Published in: Cell death & disease 2018-07, Vol.9 (8), p.806-16, Article 806
• Main Authors: Jeong, Seong-In, Kim, Jung-Wook, Ko, Kyung-Phil, Ryu, Byung-Kyu, Lee, Min-Goo, Kim, Hyo-Jong, Chi, Sung-Gil
• Format: Article
• Language: English
• Subjects: 38; 38/109; 42; 96; 96/109; 96/2; 96/21; 96/31; 96/95; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; C-Terminus; Cancer; Cell Biology; Cell Culture; CHIP protein; Feedback; Gene silencing; Growth factors; Hsc70 protein; Immunology; Interferon regulatory factor; Interferon regulatory factor 1; Invasiveness; Life Sciences; Malignancy; NF-κB protein; Promoters; Tumor cell lines; Tumor cells; Tumor suppressor genes; Tumorigenesis; Tumors; Ubiquitination; XIAP protein; Zinc finger proteins
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0867-4

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.