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
Career Transition Award (K99)
Project #
5K99CA158582-02
Application #
8333963
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2011-09-16
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$149,904
Indirect Cost
$11,104
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Gao, Tao; Zhou, Dawang; Yang, Chenghua et al. (2013) Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144:1543-53, 1553.e1
Tzatsos, Alexandros; Paskaleva, Polina; Ferrari, Francesco et al. (2013) KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J Clin Invest 123:727-39