Epigenetic mechanisms play a key role in cancer and are a major contributor in driving the aberrantly high levels of oncogenic receptor tyrosine kinases (RTK) in cancer. Understanding mechanisms leading to altered transcription of oncogenes and tumor suppressors has the potential to provide new therapeutic targets. Here we show that the PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a tumor suppressor that directly dephosphorylates and inactivates Akt, has an additional function of regulating approximately 10% of the transcriptome. Specifically, we used non-biased high-throughput RNA-sequencing and chromatin immunoprecipitation-sequencing techniques to analyze genome-wide mRNA levels and acetylation patterns of genes in cells from wild-type and PHLPP1 knockout mice. De novo motif analysis of the promoter for the genes regulated by PHLPP1 identified enrichment in the recognition motifs for a number of transcription factors, including ones involved in inflammatory signaling. Biochemical analysis revealed that PHLPP1 regulates the phosphorylation and activation of these transcription factors, such that loss of PHLPP1 leads to enhanced inflammatory signaling. Our data support a model in which PHLPP1 dephosphorylates specific transcription factors to act as the brakes to inflammatory signaling, a hallmark of cancer.
Citation Format: Ksenya Cohen Katsenelson, Joshua D. Stender, Christopher K. Glass, Alexandra C. Newton. Tumor suppressor phosphatase PHLPP1 regulates transcription factor activity and gene expression in inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4488. doi:10.1158/1538-7445.AM2017-4488