Fig. 7: Schema depicting MUC1-C involvement in activating STAT1 signaling and the type I and II IFN pathways in driving APOBEC3 and HERV expression.

Treatment of NSCLC EGFR-mutant cells with OSI is associated with induction of MUC1-C expression and OSI resistance [22]. MUC1-C functions as a common effector of the OSI-resistant phenotype linked to EMT, MET amplification and secondary EGFR mutations [22]. The present work extends those findings by demonstrating that MUC1-C drives STAT1 in the response of NSCLC cells to OSI treatment. MUC1-C/STAT1 complexes activate the MUC1 gene at a pELS region in an auto-inductive inflammatory pathway [23]. Here, we found that the MUC1 pELS-1 domain is regulated by U-ISGF3 complexes. Our results further demonstrate that the MUC1-C→U-ISGF3 pathway drives ISG A3A and A3G expression. Of significance in this regard, U-ISGF3 also activates ISGs that confer resistance to DNA damage and viruses [61]. Given that MUC1 and A3s co-evolved to protect against viruses, one notion was that MUC1-C→STAT1 signaling could link activation of A3s with induction of HERVs. Indeed, we found that MUC1-C induces HERV-K102/108 by activation of the IFN type II pathway and the formation of U-GAF complexes. These findings supported a model in which MUC1-C integrates induction of A3s and HERVs by a common STAT1-mediated mechanism. Dysregulation of A3 and HERV-K expression has been linked to genomic instability. Along these lines, our results demonstrate that MUC1-C integrates activation of A3 and HERV-K by a shared STING/STAT1-dependent auto-inductive pathway that has the potential for driving A3-induced mutagenesis and treatment resistance. A common denominator among these highly interrelated pathways is that MUC1-C/U-ISGF3 IFN type I complexes integrate activation of the MUC1 pELS-1 inflammatory domain and A3 expression, which could conceivably be in response to MUC1-C/STAT1 IFN type II-mediated induction of HERV-Ks.