Journal
CANCER RESEARCH
Volume 73, Issue 15, Pages 4950-4959Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-0370
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Funding
- Natural Science Foundation of China [30970586, 31270829]
- Chinese Academy of Sciences [KSCX2-EW-R-09]
- Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [2012CSP003]
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TNF receptor (TNFR)-associated factor TRAF6 is a key activator of NF-kappa B, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses. TRAF6 interactions determine receptor-induced cell death versus survival. TRAF6 has been implicated in cancer but its contributions have not been investigated deeply. In this study, we show that TRAF6 upregulates expression of hypoxia-inducible factor (HIF)-1 alpha. TRAF6 affects HIF-1 alpha protein levels but has little effect on mRNA level. TRAF6 increases HIF-1 alpha protein independent of oxygen. We found that TRAF6 binds HIF-1 alpha and mediates its K63-linked polyubiquitination. The E3 ligase activity of TRAF6 was required to increase HIF-1 alpha protein levels. Finally, we showed that TRAF6 promoted tumor angiogenesis and growth. Our results reveal how TRAF6 functions to upregulate HIF-1 alpha expression and promote tumor angiogenesis. Cancer Res; 73(15); 4950-9. (C) 2013 AACR.
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