The connections between hypoxia pathway signaling and the development of cancer are nowhere more relevant than in renal cell carcinoma. Hypoxia, the reduction in oxygen content in tissues, leads to the stabilization of the transcriptio factors Hypoxia-inducible factor 1 (HIF1) and Hypoxia-inducible factor 2 (HIF2) which normally result in the transcriptional activation of a genetic program that results in transient metabolic adaptation. In human clear cell renal cell carcinoma (ccRCC), this pathway is co-opted by mutations in the Von Hippel Lindau gene (VHL), which normally mediates rapid proteosomal degradation of HIF under conditions of normal oxygen levels. Without VHL activity, HIF accumulates as under conditions of hypoxia, translocates to the nucleus and activates a transcriptional program. However, the HIF transcriptional program induced by hypoxia is not identical to the HIF transcriptional program associated with aberrant HIF expression. The mechanisms resulting in retargeting of these transcription factors are unknown. However, recently deep sequencing efforts have identified recurrent mutations in genes encoding epigenetic regulators, including chromatin remodeling complex members and enzymes that modify histones. The recurrent nature of these events suggests that they are relevant to cancer development, rather than bystander mutations. However, the role of these mutations in ccRCC remains unknown. We hypothesize that mutations of epigenetic regulators identified in ccRCC alter chromatin context resulting in oncogenic retargeting of HIF1 and HIF2. We propose to identify differentially regulated HIF targeting sites and affected transcripts to identify individul genes or collections of genes that are specifically associated with pathological HIF stabilization. We furthermore propose to examine the individual contributions of histone methylation modifier genes and members of the chromatin remodeling complex recently identified as mutated in commonly in ccRCC to this retargeting and explore the implications in human tumor chromatin packaging.

Public Health Relevance

This proposal examines the interrelationships between epigenetic modification of chromatin and HIF transcriptional activation in cancer. We propose to identify differentially regulated HIF targeting sites and affected transcripts to identify individul genes or collections of genes that are specifically associated with pathological HIF stabilization. We furthermore propose to examine the individual contributions of histone methylation modifier genes and members of the chromatin remodeling complex recently identified as mutated in commonly in ccRCC to this retargeting and explore the implications in human tumor chromatin packaging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166447-04
Application #
8848792
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Okano, Paul
Project Start
2012-05-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Slaughter, Mariesa J; Shanle, Erin K; McFadden, Andrew W et al. (2018) PBRM1 bromodomains variably influence nucleosome interactions and cellular function. J Biol Chem 293:13592-13603
McDaniel, Stephen L; Hepperla, Austin J; Huang, Jie et al. (2017) H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity. Cell Rep 19:2371-2382
Pattenden, Samantha G; Simon, Jeremy M; Wali, Aminah et al. (2016) High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility. Proc Natl Acad Sci U S A 113:3018-23
Hacker, Kathryn E; Fahey, Catherine C; Shinsky, Stephen A et al. (2016) Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation. J Biol Chem 291:21283-21295
Gomez, Nicholas C; Hepperla, Austin J; Dumitru, Raluca et al. (2016) Widespread Chromatin Accessibility at Repetitive Elements Links Stem Cells with Human Cancer. Cell Rep 17:1607-1620
Park, In Young; Powell, Reid T; Tripathi, Durga Nand et al. (2016) Dual Chromatin and Cytoskeletal Remodeling by SETD2. Cell 166:950-962
Roode, Luke E; Brighton, Hailey; Bo, Tao et al. (2016) Subtumoral analysis of PRINT nanoparticle distribution reveals targeting variation based on cellular and particle properties. Nanomedicine 12:1053-1062
Scelo, G; Hofmann, J N; Banks, R E et al. (2016) International cancer seminars: a focus on kidney cancer. Ann Oncol 27:1382-5
Simon, Jeremy M; Parker, Joel S; Liu, Feng et al. (2015) A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin. J Biol Chem 290:26088-102
Orvis, Tess; Hepperla, Austin; Walter, Vonn et al. (2014) BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. Cancer Res 74:6486-6498

Showing the most recent 10 out of 21 publications