Abstract 771: Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.

The c-Myc oncoprotein is generally considered to be a master regulator of gene transcription by virtue of its ability to activate or repress the expression of a large percentage of all genes. However, mechanisms that direct c-Myc9s recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl-isomerase regulates c-Myc transcriptional activity by altering c-Myc9s association with target gene promoters. Specifically, we show that Pin1 enhances the recruitment of Serine62-phosphorylated c-Myc along with its co-activators to selected target gene promoters during gene activation, followed by promoting c-Myc9s release associated with its degradation, resulting in cyclic c-Myc DNA binding. This facilitates c-Myc9s activation of target genes associated with an increase in elongating RNA Polymerase II in the gene body. Genes impacted by this mechanism are involved in cell growth and metabolism, resulting in enhanced pro-proliferative activity, even while controlling c-Myc expression. In cancer cells with impaired c-Myc degradation, Pin1 still regulates cyclic c-Myc DNA binding, even though it no longer enhances c-Myc degradation. This allows for simultaneous high expression of Pin1 and c-Myc in cancer, which can drive a gene expression pattern that we show is enriched in poor outcome subtypes of breast cancer. This study provides new insight into mechanisms regulating c-Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in transcription factor regulation, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and c-Myc. Citation Format: Amy Farrell, Carl Pelz, Xiaoyan Wang, Colin Daniel, Yulong Su, Mahnaz Janghorban, Soren Impey, Rosalie C. Sears. Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 771. doi:10.1158/1538-7445.AM2013-771