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Tumor Suppressor Phosphatase PHLPP Regulates Gene Expression through Suppression of Transcription Factor Activation

Ksenya Cohen Katsenelson
Appointment Period: 2016-2017, Grant Year: [31]

Ksenya Katsenelson

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. We have recently made the fundamental discovery that PH domain leucine-rich repeat protein phosphatase (PHLPP), a tumor suppressor that directly dephosphorylates and inactivates Akt, has an additional function of regulating approximately 10% of the transcriptome. Specifically, PHLPP suppresses the transcription of RTKs such as the EGF receptor (EGFR), thus dampening the signaling output of oncogenic growth factor signaling (1). Even more importantly, our data uncover PHLPP as a major regulator of histone post-translational modifications, one of the main epigenetic mechanisms by which gene expression is controlled. In our on-going studies, in collaboration with the lab of Dr. Chris Glass, we use non-biased high-throughput RNA-sequencing and chromatin immunoprecipitation-sequencing techniques to analyze genome-wide mRNA levels and acetylation and phosphorylation 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 reveals 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. This novel epigenetic mechanism for PHLPP, to control mRNA and hence protein levels in cells has enormous clinical relevance. First, RTKs are upregulated in diverse cancers, so PHLPP could be a novel therapeutic target to reduce aberrant growth factor signaling. Second, the identification of PHLPP as a regulator of histone modifications has potential for developing therapies to overcome aberrant epigenetic control of gene activity.

PUBLICATIONS (resulting from this training)

Reyes G, Niederst M, Cohen-Katsenelson K, Stender JD, Kunkel MT, Chen M, Brognard J, Sierecki E, Gao T, Nowak DG, Trotman LC, Glass CK, Newton AC. (2014) Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci USA 111(38):E3957-65. doi: 10.1073/pnas.1404221111. PMID: 25201979 PMCID: PMC4183331

Cohen Katsenelson K, Newton AC. Moving beyond Akt: expanding roles of PHLPP in cell signaling. (2018) Curr Top Microbiol Immunol. In Press.

Nowak DG, Cohen Katsenelson K, Watrud K, Ambrico AJ, Chen M, D’Andrea VD, Casanova-Salas I, Pan CH, Wilkinson JE, Newton AC, Trotman LC. (2018) The PHLPP2 phosphatase is a druggable driver of prostate cancer metastasis. In review in eLife.

Cohen-Katsenelson K, Stender JD*, Uchiyama S, Grezchnik A, Nizet V, Glass C, Newton AC. PH domain Leucine rich repeat Protein Phosphatase 1 (PHLPP1) Suppresses Inflammatory Signaling Mediated by STAT1. In preparation for Molecular Cell.