Cancer cells are characterized by reprogramming of nutrient metabolism to support growth and proliferation and by epigenetic alterations that impact gene expression and genomic integrity. An emerging paradigm for epigenetic regulation of the genome is that chromatin modifications can be regulated by cellular metabolism. For example, glucose availability and production of acetyl-CoA by the enzyme ATP-citrate lyase (ACL) can modulate global levels of histone acetylation. The effects of oncogene-induced metabolic reprogramming on the cancer cell epigenome are largely unknown, however. The phosphoinositide 3-kinase-Akt pathway is frequently activated in cancer, and is a key regulator of glucose uptake and glycolysis. Akt can also directly activate ACL through phosphorylation, potentially facilitating acetyl-CoA production during nutrient limitation. We hypothesize that Ak-induced metabolic reprogramming influences histone acetylation, thereby impacting gene expression and proliferation in cancer cells. The goals of this proposal are to define the mechanisms linking nutrient availability to histone acetylation and to elucidate the impact of Akt activation on acetyl-CoA production, genome-wide histone acetylation, and gene expression in glioblastoma cells.
Three specific aims are proposed: 1) determine the mechanisms underlying ACL-dependent regulation of histone acetylation in cancer cells~ 2) investigate the role of Akt-induced metabolic reprogramming in modulating acetyl-CoA production and utilization in cancer cells~ 3) examine the effects of Akt activation and glucose availability on gene expression and the epigenome.

Public Health Relevance

Mechanisms underlying epigenetic alterations in cancer cells are poorly understood. We propose to investigate the hypothesis that oncogene-induced metabolic reprogramming plays a role in regulating the cancer cell epigenome. This work will provide fundamental information about the link between cancer cell metabolism and epigenetics and has the potential to point towards metabolic or epigenetic features of cancer cells that may enhance tumor susceptibility to epigenetic therapies such as histone deacetylase inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174761-01A1
Application #
8696293
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Okano, Paul
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$332,000
Indirect Cost
$124,500
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104