Transcription Factor AP-2α Activates RNA Polymerase III–directed Transcription and Tumor Cell Proliferation by Controlling Expression of C-Myc and P53

Deregulation of transcription factor AP2 alpha (TFAP2A) and RNA polymerase III (Pol III) products is associated with tumorigenesis. However, the mechanism underlying this event is not fully understood and the connection between TFAP2A and Pol III-directed transcription has not been investigated. Here, we report that TFAP2A functions as a positive factor in the regulation of Pol III-directed transcription and cell pro-liferation. We found TFAP2A is also required for the activation of Pol III transcription induced by the silencing of filamin A, a well-known cytoskeletal protein and an inhibitor in Pol III- dependent transcription identified previously. Using a chro-matin immunoprecipitation technique, we showed TFAP2A positively modulates the assembly of Pol III transcription ma-chinery factors at Pol III-transcribed gene loci. We found TFAP2A can activate the expression of Pol III transcription-related factors, including BRF1, GTF3C2, and c-MYC. Furthermore, we demonstrate TFAP2A enhances expression of MDM2, a negative regulator of tumor suppressor p53, and also inhibits p53 expression. Finally, we found MDM2 over-expression can rescue the inhibition of Pol III-directed tran-scription and cell proliferation caused by TFAP2A silencing. In summary, we identified that TFAP2A can activate Pol III- directed transcription by controlling multiple pathways, including general transcription factors, c-MYC and MDM2/ p53. The findings from this study provide novel insights into the regulatory mechanisms of Pol III-dependent transcription and cancer cell proliferation.