Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1)

• Published in: The Journal of biological chemistry Vol. 293; no. 29; pp. 11401 - 11414
• Main Authors: Noguchi, Ken, Dincman, Toros A., Dalton, Annamarie C., Howley, Breege V., McCall, Buckley J., Mohanty, Bidyut K., Howe, Philip H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.07.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Cell Line, Tumor; Cells, Cultured; cytokine; Cytokines - genetics; Epithelial-Mesenchymal Transition; epithelial-mesenchymal transition (EMT); FAM3C; Gene Expression Regulation, Neoplastic; Gene Regulation; Humans; ILEI; interleukin-like EMT inducer; melanoma; Melanoma - genetics; Melanoma - pathology; Mice; mRNA; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Proteins - genetics; phenotype switching; transcription factor; Transcriptional Activation; Up-Regulation; Upstream Stimulatory Factors - genetics; USF-1; cytokine; epithelial-mesenchymal transition (EMT); transcription factor; ILEI; phenotype switching; USF-1; melanoma; mRNA; FAM3C; interleukin-like EMT inducer
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.003616

Interleukin-like EMT inducer (ILEI, FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell-biological process that confers metastatic properties to a tumor cell. However, very little is known about how ILEI is regulated. Here we demonstrate that ILEI is an in vivo regulator of melanoma invasiveness and is transcriptionally up-regulated by the upstream stimulatory factor-1 (USF-1), an E-box–binding, basic-helix-loop-helix family transcription factor. shRNA-mediated knockdown of ILEI in melanoma cell lines attenuated lung colonization but not primary tumor formation. We also identified the mechanism underlying ILEI transcriptional regulation, which was through a direct interaction of USF-1 with the ILEI promoter. Of note, stimulation of endogenous USF-1 by UV-mediated activation increased ILEI expression, whereas shRNA-mediated USF-1 knockdown decreased ILEI gene transcription. Finally, we report that knocking down USF-1 decreases tumor cell migration. In summary, our work reveals that ILEI contributes to melanoma cell invasiveness in vivo without affecting primary tumor growth and is transcriptionally up-regulated by USF-1.