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Regulation of the LEF1 gene's alternative promoter

LEF1 is a DNA‐binding transcription factor and a downstream component of the Wnt signaling pathway. The LEF1 gene has multiple promoters and produces two distinct proteins: a full‐length, growth‐promoting form produced from promoter 1 (P1), LEF1, and a truncated, growth‐suppressing form produced from promoter 2 (P2), dnLEF1. In tissues where LEF1 is normally expressed, both promoters are active, producing both forms of LEF1. However, in colon cancer, LEF1 is aberrantly expressed, and only the full‐length, growth‐promoting protein is produced. P1 is a Wnt target, explaining its transcriptional upregulation in Wnt‐driven colon cancers. P2 is silent because it is actively repressed. A genomic region upstream of P2 that is necessary for its repression has been delimited, however, the protein components and exact mechanism of repression are unknown. In this study we describe one component of the repressor machinery, identified through site‐directed mutagenesis of the LEF1 core promoter 2. A YY1 binding site at the +25 location was identified, which, when mutated, greatly reduces repressor function. The binding of YY1 to the +25 site in vitro is shown by gel shift, while ChIP suggests in vivo binding of YY1 within a colon cancer cell line. The functional role of YY1 is confirmed through siRNA knockdown of YY1, which results in loss of repressor function. These findings suggest a pivotal role for YY1 in repression of P2.