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.
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.
|Kai, Yan; Andricovich, Jaclyn; Zeng, Zhouhao et al. (2018) Predicting CTCF-mediated chromatin interactions by integrating genomic and epigenomic features. Nat Commun 9:4221|
|Andricovich, Jaclyn; Perkail, Stephanie; Kai, Yan et al. (2018) Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. Cancer Cell 33:512-526.e8|
|Chen, Jian; Shukla, Vivek; Farci, Patrizia et al. (2017) Loss of the transforming growth factor-? effector ?2-Spectrin promotes genomic instability. Hepatology 65:678-693|
|Andricovich, Jaclyn; Kai, Yan; Peng, Weiqun et al. (2016) Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J Clin Invest 126:905-20|
|Andricovich, Jaclyn; Kai, Yan; Tzatsos, Alexandros (2016) Lysine-specific histone demethylases in normal and malignant hematopoiesis. Exp Hematol 44:778-82|
|Chen, Jian; Katz, Lior H; Muñoz, Nina M et al. (2016) Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-?/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation. Sci Rep 6:30217|
|Papageorgis, Panagiotis; Ozturk, Sait; Lambert, Arthur W et al. (2015) Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis. Breast Cancer Res 17:98|