title: Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells.
abstract: The xCT light chain of the cystine/glutamate transporter (system XC-) 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 XC- 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.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Department of Gastrointestinal Surgery, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka City, Osaka, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Ashujit
authors.initials: A
authors.lastname: Tagde
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000595:Amino Acid Sequence; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D049109:Cell Proliferation; D003553:Cystine / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D018396:Mucin-1 / Q000378:metabolism*; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D027182:Amino Acid Transport System y+; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C060192:MUC1 protein, human; D018396:Mucin-1; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D003553:Cystine
keywords: CD44v; MUC1-C; epigenetics; ferroptosis; xCT