Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

The most effective, intrinsic, protective force against disseminated tumor cells is the immune system. Immune cells rely heavily on JAK/STAT signaling to direct cellular responses upon cytokine stimulation. Compared to other adult tissues, hematopoietic cells have significantly higher endogenous levels of NMI mRNA indicating that NMI may play an integral role in the function of these cells. 1 The first study that identified NMI's ability to enhance or alter activity of transcription factors described NMI's effect on signal transducer and activator (STAT) proteins. NMI interacts with all STATs except STAT2 in activated peripheral blood lymphocytes. 65 The interaction between STAT1 or STAT5 and NMI significantly increased the activity of their respective target gene luciferase reporters. 65 STAT1 activity promotes an inflammatory antitumor immune response in innate immune cells, such as dendritic cells or macrophages. 66 Furthermore, STAT1 signaling stimulates the T helper 1 phenotype in CD41 T cells of the adaptive immune system, creating an inflammatory response through the production of IFNg. 66 STAT5, on the other hand, impacts differentiation of CD81 T cells, CD41 Th1 versus Th2 differentiation and development of regulatory T cells. 67 It is feasible that modulation of STAT1 or STAT5 activity by NMI impacts the maturation of innate and adaptive immune cells. Interestingly, the activity of STAT1 and STAT5 reporters was enhanced further when the histone acetyltransferases, CBP and p300, were independently co-transfected; and it was proposed that NMI enhances the interaction between STATs and CBP/p300. 65 This study suggests that NMI facilitates binding between epigenetic modifiers and transcription factors to enhance transcription of downstream target genes. The specific contribution of NMI to the anti-tumor immune response is an area that has not been studied.