Recently, we made a provocative and novel discovery in our laboratory that a muscle-specific protein, myoferlin, is markedly upregulated in head and neck cancer cells. Myoferlin is a member of ferlin family of membrane proteins and most of the studies related to myoferlin's biological and molecular function(s) were carried out on muscle cells, as it was assumed that myoferlin is predominantly present only in the muscle cells. Recent studies have shown that myoferlin is also expressed in endothelial and cancer cells and it modulates VEGFR-2 and EGFR stability and function. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we observed that myoferlin is bound to EHD2 protein in the resting cells and when the cells are treated with IL-6, myoferlin dissociates from EHD2 and binds to activated STAT3. Interestingly, myoferlin knock-down did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus and expression of its target proteins including Snail and Nanog. In addition, inhibition of STAT3 phosphorylation by phosphorylation defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis, in vivo. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.
Citation Format: Arti Yadav, Bhavna Kumar, Theodoros N. Teknos, Pawan Kumar. A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1148.