Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells

Abstract

// Masanori Hasegawa 1 , Hidekazu Takahashi 1,3 , Hasan Rajabi 1 , Maroof Alam 1 , Yozo Suzuki 1,4 , Li Yin 1 , Ashujit Tagde 1 , Takahiro Maeda 1 , Masayuki Hiraki 1 , Vikas P. Sukhatme 2 and Donald Kufe 1 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 2 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 3 Department of Gastrointestinal Surgery, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan 4 Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka City, Osaka, Japan Correspondence to: Donald Kufe, email: // Keywords : xCT, MUC1-C, CD44v, epigenetics, ferroptosis Received : December 11, 2015 Accepted : January 26, 2016 Published : February 22, 2016 Abstract The xCT light chain of the cystine/glutamate transporter (system X C - ) is of importance for the survival of triple-negative breast cancer (TNBC) cells. The MUC1-C transmembrane oncoprotein is aberrantly overexpressed in TNBC and, like xCT, has been linked to maintaining glutathione (GSH) levels and redox balance. However, there is no known interaction between MUC1-C and xCT. Here we show that silencing MUC1-C is associated with decreases in xCT expression in TNBC cells. The results demonstrate that MUC1-C forms a complex with xCT and the CD44 variant (CD44v), which interacts with xCT and thereby controls GSH levels. MUC1-C binds directly with CD44v and in turn promotes stability of xCT in the cell membrane. The interaction between MUC1-C and xCT is further supported by the demonstration that targeting xCT with silencing or the inhibitor sulfasalazine suppresses MUC1 gene transcription by increasing histone and DNA methylation on the MUC1 promoter. In terms of the functional significance of the MUC1-C/xCT interaction, we show that MUC1-C protects against treatment with erastin, an inhibitor of X C - and inducer of ferroptosis, a form of non-apoptotic cell death. These findings indicate that targeting this novel MUC1-C/xCT pathway could represent a potential therapeutic approach for promoting TNBC cell death.