MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells

// Akriti Kharbanda, Hasan Rajabi, Caining Jin, Maroof Alam, Kwok-Kin Wong, Donald Kufe Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 Correspondence to: Dr. Donald Kufe, e-mail: donald_kufe@dfci.harvard.edu . Key words: KRAS, NSCLC, MUC1-C, AKT, ZEB1, EMT, self-renewal Abbreviations: NSCLC, non-small cell lung cancer; MUC1, mucin 1; MUC1-C, MUC1 C-terminal subunit; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition Received: July 19, 2014 Accepted: August 17, 2014 Published: August 22, 2014 ABSTRACT Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC→AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal.