Eukaryotic gene transcription is influenced by chromatin modifications that are under the control of epigenetic regulatory proteins. In addition to genetic alterations, it is now apparent that epigenetic mechanisms are also central to cancer pathogenesis. Epigenetic alterations are heritable, drive neoplastic progression, and undergo the same selective pressure as genetic alterations. Therefore identifying the key epigenetic regulators in cancers should point to new and better therapeutic approaches. An integrative biology approach has been employed to identify and dissect the role that families of histone modifying enzymes play in the development of pancreatic ductal adenocarcinoma (PDAC), the 4th most common cause of cancer death in the United States. This unbiased genetic screen led the discovery of the family of jumonji-domain histone demethylases (HDMs) as important regulators of PDAC. In particular, it has been found that the HDM, KDM2B, was highly upregulated in PDAC and was required for the tumorigenicity of PDAC cell lines and the immortalization and transformation of primary cells. By using gain- and loss-of-function approaches and genetically engineered mouse models we propose to delineate the molecular mechanisms by which KDM2B contributes to PDAC initiation, progression, and maintenance by defining key target genes and establishing the functional interaction between KDM2B and other chromatin modifying enzymes. Given the reversibility of histone methylation and the importance of the Jumonji domain, KDM2B -unlike many other oncogenic transcriptional regulators- represents an attractive candidate for the development of small molecule inhibitors.

Public Health Relevance

In addition to genetic alterations, epigenetic mechanisms are also central to cancer pathogenesis. Epigenetic alterations are heritable, drive neoplastic progression, and undergo the same selective pressure as genetic alterations. Identifying the key epigenetic regulators in cancer should point to new and better therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA158582-03
Application #
8821100
Study Section
Special Emphasis Panel (NSS)
Program Officer
Okano, Paul
Project Start
2014-05-20
Project End
2017-04-30
Budget Start
2014-05-20
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$241,530
Indirect Cost
$81,577
Name
George Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052