Dysregulated D-dopachrome Tautomerase, a Hypoxia-inducible Factor-dependent Gene, Cooperates with Macrophage Migration Inhibitory Factor in Renal Tumorigenesis

Background: DDT is a novel member of the MIF cytokine family with overlapping functions. Results: DDT is a direct HIF target gene that is expressed widely in renal carcinoma and contributes to tumorigenesis. Conclusion: DDT has greater tumor-promoting properties than MIF and may compensate for MIF inhibition. Significance: Efforts to inhibit MIF signaling in cancer need to target DDT as well. Clear cell renal cell carcinomas (ccRCCs) are characterized by biallelic loss of the von Hippel-Lindau tumor suppressor and subsequent constitutive activation of the hypoxia-inducible factors, whose transcriptional programs dictate major phenotypic attributes of kidney tumors. We recently described a role for the macrophage migration inhibitory factor (MIF) in ccRCC as an autocrine-signaling molecule with elevated expression in tumor tissues and in the circulation of patients that has potent tumor cell survival effects. MIF is a pleiotropic cytokine implicated in a variety of diseases and cancers and is the target of both small molecule and antibody-based therapies currently in clinical trials. Recent work by others has described D-dopachrome tautomerase (DDT) as a functional homologue of MIF with a similar genomic structure and expression patterns. Thus, we sought to determine a role for DDT in renal cancer. We find that DDT expression mirrors MIF expression in ccRCC tumor sections with high correlation and that, mechanistically, DDT is a novel hypoxia-inducible gene and direct target of HIF1 and HIF2. Functionally, DDT and MIF demonstrate a significant overlap in controlling cell survival, tumor formation, and tumor and endothelial cell migration. However, DDT inhibition consistently displayed more severe effects on most phenotypes. Accordingly, although dual inhibition of DDT and MIF demonstrated additive effects in vitro, DDT plays a dominant role in tumor growth in vivo. Together, our findings identify DDT as a functionally redundant but more potent cytokine to MIF in cancer and suggest that current attempts to inhibit MIF signaling may fail because of DDT compensation.