Androgen and its receptor AR, which is a member of the human nuclear receptor (NRs) superfamily, play critical roles in prostate cancer (PC) and castrate resistant prostate cancer (CRPC) that kills thousands of people world-wide. We posit that a better understanding of NR signaling pathway and its integration in epigenomic signaling are keys for development of future therapeutics of this deadly disease. The long term goal of our research is to discover novel components of NR function in transcriptional and epigenomic regulation with strong translational implications in human diseases. The protein kinase termed PKN1 plays a critical role in AR dependent gene regulation by establishing an epigenomic marking (histone H3 threonine 11 phosphorylation (H3T11P)) on nucleosomes at AR target genes. We hypothesize that the PKN1-H3T11P- WDR5 signaling module plays a previously unrealized and critical role in castrate resistant prostate cancer (CRPC). The goal of this present work is to perform in depth and integrative mechanistic, genome-wide, cellular and animal based studies to dissect the role of this newly discovered signaling module in AR function in CRPC. To achieve our research goals, we will utilize interdisciplinary knowledge and complementary expertise of the co-investigators spanning biochemistry, patho-physiology, genome biology, animal and cellular models of PC and molecular biology.
In Specific Aims, we will examine in extensive molecular details the role of WDR5, and PKN1 in gene regulation, and CRPC-cell function in vitro and in vivo using cell and animal based models. We will also determine the gene-specific and genome-wide localization profiles of WDR5 and H3T11P in CRPC cells. Epigenomic markings and identification of their effector proteins in hormone action are new and rapidly evolving concepts and we believe our work lies at the limit of current knowledge of hormone signaling. Our findings will thus significantly advance the field by providing a better understanding of the role of epigenomic modifications and their effector proteins in nuclear receptor action and in human diseases including CRPC.

Public Health Relevance

Steroid hormone and vitamin signaling that functions primarily via nuclear hormone receptors have profound effects on human physiology and diseases including cancer. Androgen and its receptor play critical roles in prostate cancer and castrate resistant prostate cancer (CRPC), which is a major cause of cancer death in men worldwide. Our proposed studies will provide a deeper understanding of how epigenomic modifications and their effector proteins modulate nuclear receptor target genes, cell proliferation and CRPC development, and may lead to the development of novel therapeutic drugs that target our epigenome to treat CRPC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA196270-04
Application #
9512860
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Ault, Grace S
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kim, Ji-Young; Yu, Jindan; Abdulkadir, Sarki A et al. (2016) KAT8 Regulates Androgen Signaling in Prostate Cancer Cells. Mol Endocrinol 30:925-36