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Opposite lineage-specific regulation of tumor progression by the same transcription factor is an understudied phenomenon. Here, we report that levels of a carcinoma oncogenic transcription factor FOXQ1 are decreased during melanoma progression. Moreover, in melanoma cells, FOXQ1 suppresses the same processes it activates in carcinoma cells: epithelial-to-mesenchymal transition, invasion, and metastasis. We identify that lineage-specific tumor suppressor or oncogenic functions of FOXQ1 in large part depend on its ability to repress or activate expression of the same gene (N-cadherin, (CDH2)) in melanoma or carcinoma cells, respectively. Mechanistically, we demonstrate that FOXQ1 interacts with nuclear β-catenin and TLE proteins, and that repression of CDH2 by FOXQ1 occurs in the presence of TLE and absence of nuclear β-catenin, levels of which are lower in human melanomas than carcinomas. Accordingly, FOXQ1-dependent phenotypes can be manipulated by altering nuclear β-catenin or TLE proteins levels. Our data identify a novel melanoma suppressor and establish a unique mechanism underlying inverse lineage-specific transcriptional regulation of transformed phenotypes.

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.