PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple phenotypes including cancer, changes in stem cell biology and alteration of fundamental processes such as proliferation and apoptosis. We have recently determined that the PI3K pathway activates the transcriptional repressor NFIL3/E4BP4. NFIL3 is over expressed in human breast cancers lacking PTEN. Moreover, over expression of NFIL3 is seen in multiple types of poor-prognosis cancer. We have shown that NFIL3 binds and recruits HDAC2 to promoters to deacetylate histones and silence genes and even represses a recently recognized pool of nuclear FOXO proteins at multiple FOXO target genes. Our findings have broad implications that suggest that NFIL3, which represses numerous non-FOXO targets, could mediate reprogramming of chromatin as a consequence of PTEN mutation. This application will use a combination of biochemistry, signal transduction, mouse genetics, and cancer cell biology to address the following goals 1) to understand the mechanism by which NFIL3 alters the epigenetic regulation of target genes, 2) to determine the contribution of NFIL3 to changes in gene expression and chromatin modification caused by genetic ablation of PTEN, 3) to demonstrate the contribution of NFIL3 to tumor and other phenotypes due to PTEN mutation in mice and cells, and 4) to define how NFIL3 is regulated by PTEN and its implication for PI3K- based cancer therapy.
Analysis of human tumors has shown that the PI3K pathway is one of the most frequently activated pathways in many forms of malignancy. Here we will define an important mechanism of PI3K regulation of NFIL3 that appears to be responsible for modulating chromatin in a PI3K- dependent manner. This work has important implications for cancer and stem cell biology.
|Mathur, Deepti; Stratikopoulos, Elias; Ozturk, Sait et al. (2017) PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition. Cancer Discov 7:380-390|
|Pappas, Kyrie; Xu, Jia; Zairis, Sakellarios et al. (2017) p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes. Mol Cancer Res 15:1051-1062|
|Chung, Chi-Yeh; Sun, Zhen; Mullokandov, Gavriel et al. (2016) Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis. Cell Rep 16:472-486|
|Stratikopoulos, Elias E; Parsons, Ramon E (2016) Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue. Clin Cancer Res 22:2605-10|
|She, Qing-Bai; Gruvberger-Saal, Sofia K; Maurer, Matthew et al. (2016) Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer 16:587|
|Nguyen, H-N; Yang Jr, J-M; Rahdar, M et al. (2015) A new class of cancer-associated PTEN mutations defined by membrane translocation defects. Oncogene 34:3737-43|
|Stratikopoulos, Elias E; Dendy, Meaghan; Szabolcs, Matthias et al. (2015) Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy. Cancer Cell 27:837-51|
|Keniry, Megan; Dearth, Robert K; Persans, Michael et al. (2014) New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond. Discoveries (Craiova) 2:e15|
|Hopkins, Benjamin D; Parsons, Ramon E (2014) Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy. Clin Cancer Res 20:5379-83|
|Hodakoski, Cindy; Hopkins, Benjamin D; Barrows, Douglas et al. (2014) Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc Natl Acad Sci U S A 111:155-60|
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