Abstract 1036: A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
Authors: Yadav Arti , Kumar Bhavna , Teknos Theodoros N. , Kumar Pawan 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and five-year survival rates (&lt;50%) are among the lowest of the major cancers. Although advancements in the anti-cancer treatments including surgery, radiation and chemotherapy have increased the local control of HNSCC, the overall survival rates have not improved significantly over the last three decades. This poor outcome becomes even worse (20%, 5-year survival rate) for advanced HNSCC patients that have become resistant to standard chemoradiation treatment. Therefore, there is an urgent need to identify new therapeutic targets so that novel treatment regimen(s) can be developed to improve the therapeutic efficacy while minimizing the toxicity. 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 other cell types including endothelial cells and cancer cells. In our study, we observed that in addition to being expressed in tumor cells, myoferlin levels were further elevated in highly chemoresistant cells. Furthermore, myoferlin expression was also significantly higher in patients with HPV-negative tumors that show markedly poor clinical outcome and often develop resistance to chemotherapy as compared to HPV-positive tumors that normally respond better to traditional chemotherapy. Knockdown of myoferlin in head and neck cancer cells by siRNA significantly reversed chemoresistance and markedly decreased ALDH positive cancer stem cell population. These results suggest that myoferlin might be a contributing factor in the aggressive and metastatic phenotype in HNSCC. Our mechanistic studies demonstrate a novel role for myoferlin in cancer cells. Our results showed that myoferlin is bound to EHD2 protein in the resting cancer cell. Treatment of these cancer cells with IL-6 induced STAT3 phosphorylation, which led to myoferlin dissociation from EHD2 and binding to phosphorylated 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. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated proteins to the nucleus. Taken together, our results from this study provide a novel oncogenic function of a muscle-specific protein, myoferlin, which may lead to the development of innovative therapeutic strategies to target HNSCC.
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 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2015-1036