Cancer cells exhibit alterations in parameters of nuclear architecture that control cell fate and compromise control of cell growth. Our Program has established new biological paradigms by showing that gene regulatory factors integrate cell signaling at chromatin microenvironments ('subnuclear foci') and support epigenetic mechanisms through association with mitotic chromosomes. In collaboration with other Program Project investigators. Project 1 will now establish new dimensions in gene regulation by defining perturbations in architecturally linked regulatory mechanisms during interphase and mitosis in AML and breast cancer cells. Our central hypothesis is that (i) subnuclear targeting of transcription factors to gene regulatory foci during interphase and (ii) the association of transcription factors with their target genes in mitotic chromosomes are fundamental to the retention of biological states of normal and cancer cells. Therefore, we will use IF microscopy, biochemical, genomic and proteomic approaches (i) to characterize modifications in architectural epigenetics and molecular pathological consequences of expressing the translocation-related t(8;21) AML-ETO fusion protein (Aim 1), (ii) to analyze genes that are transcriptionally and spatially controlled by Runx2 in chromatin micro-environments ('subnuclear foci') during interphase in breast cancer cells (Aim 2), and (iii) to examine Runx2 mediated architectural epigenetics in breast cancer cells by characterization of Runx2 and cognate gene regulatory factors that associate with mitotic chromosomes (Aim 3). By investigating the functional role of Runx2 in establishing chromatin micro-environments ('subnuclear foci') during interphase and architectural epigenetics in cancer cells during mitosis, we will challenge traditional biochemical views of gene regulation by defining the pathological linkages between modifications in nuclear architecture and gene expression that are fundamental to the molecular etiology of tumorigenesis.

Public Health Relevance

Changes in the overall shape and structure ofthe nucleus are pathological hallmarks of cancer cells that are linked to cellular transformation. This study will use state-of-the-art methods to characterize how targeting of oncogenic transcription factors to specific subnuclear structures and mitotic chromosomes supports gene regulation as components of a novel epigenetic mechanism ('architectural epigenetics').

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA082834-15
Application #
8444558
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
15
Fiscal Year
2014
Total Cost
$242,416
Indirect Cost
$49,111
Name
University of Vermont State Agr Coll
Department
Type
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
Araya, H├ęctor F; Sepulveda, Hugo; Lizama, Carlos O et al. (2018) Expression of the ectodomain-releasing protease ADAM17 is directly regulated by the osteosarcoma and bone-related transcription factor RUNX2. J Cell Biochem 119:8204-8219
Carver, Gary E; Locknar, Sarah A; Weaver, Donald L et al. (2018) Real-time detection of breast cancer at the cellular level. J Cell Physiol :
Tracy, Kirsten M; Tye, Coralee E; Ghule, Prachi N et al. (2018) Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer. Mol Cancer Res 16:587-598
Zaidi, Sayyed K; Fritz, Andrew J; Tracy, Kirsten M et al. (2018) Nuclear organization mediates cancer-compromised genetic and epigenetic control. Adv Biol Regul 69:1-10
Hong, Deli; Fritz, Andrew J; Finstad, Kristiaan H et al. (2018) Suppression of Breast Cancer Stem Cells and Tumor Growth by the RUNX1 Transcription Factor. Mol Cancer Res 16:1952-1964
Zaidi, Sayyed K; Nickerson, Jeffrey A; Imbalzano, Anthony N et al. (2018) Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes. Mol Cancer Res 16:1617-1624
Hong, Deli; Fritz, Andrew J; Zaidi, Sayyed K et al. (2018) Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J Cell Physiol 233:9136-9144
Farina, Nicholas H; Zingiryan, Areg; Vrolijk, Michael A et al. (2018) Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention. J Cell Physiol 233:6408-6417
Tracy, Kirsten M; Tye, Coralee E; Page, Natalie A et al. (2018) Selective expression of long non-coding RNAs in a breast cancer cell progression model. J Cell Physiol 233:1291-1299
Hong, Deli; Fritz, Andrew J; Gordon, Jonathan A et al. (2018) RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol :

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