Suppression of MHC class I gene expression by N-myc through enhancer inactivation.

Amplification of the N-myc oncogene in human neuroblastoma is associated with increased metastatic ability. We previously found that over-expression of N-myc in rat neuroblastoma tumor cells causes a dramatic reduction in the expression of MHC class I mRNA. We show here that two distinct elements in the promoter render the MHC class I genes susceptible to N-myc-mediated suppression, one of which was identified as the MHC class I gene enhancer. Our data indicate that elevated N-myc expression is associated with reduced binding of a transcription factor that activates this enhancer. As a result, the activity of the MHC class I gene enhancer is greatly diminished. Elevated expression of the N-myc oncogene in human neuroblastomas and murine pre-B lymphoid lines also correlated with reduced factor binding to the MHC class I gene enhancer. Thus, an important effect of N-myc may be to impair the function of certain cellular enhancers by altering the levels of their cognate binding proteins.