TRANSCRIPTIONAL SUPPRESSION OF HLA-B EXPRESSION BY C-MYC IS MEDIATED THROUGH THE CORE PROMOTER ELEMENTS

In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. This suppression has severe consequences for the recognition of these tumor cells by the immune system of the organism. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. The transcriptional activity of various HLA-B reporter constructs was tested in a melanoma cell line with low endogenous c-myc expression and in transfectants with high stable and transient c-myc expression. We demonstrated that the responsive region can be mapped to the core promoter region of HLA class I, ruling out any effects of c-myc overexpression on the enhancer A or enhancer B regions. The region subject to downregulation is confined to a 43 base pair fragment encompassing the CCAAT and TATA elements. By coupling this region to a heterologous viral enhancer, we showed that the downmodulation by c-Myc is independent of the presence and nature of an enhancer. These results suggest a mechanism in which c-Myc downregulates the expression of HLA class I genes by interfering with the basal level of transcription.