Prostate cancer (PCa) is the leading life-threatening malignancy in American men and is disproportionally higher in African Americans (AAs) than other ethnic populations, underscoring a need to decode the underlying mechanism and to develop new and effective therapies to cure PCa. Despite androgen- deprivation therapy, relapse occurs in many PCa patients who eventually still die. The initiation and progression of PCa are driven by dysregulation of multiple oncogenic pathways secondary to genetic and epigenetic alterations of oncogenes and tumor suppressors. PTEN (phosphatase and tension homolog deleted on chromosome ten) is frequently deleted and/or mutated in various human cancers. Loss of PTEN leads to cancers with the aberration of AKT-mTOR, SKP2, TGF-?, and androgen receptor (AR) signaling pathways. KDM5B (lysine demethylase 5B, also named JARID1B), a JmjC domain- containing H3K4 histone demethylase, activates the gene expression of FOXA1, a crucial co-factor for AR function and signaling. Aberrant elevation of KDM5B is often found in human cancers including advanced PCa. FOXA1 mutation is 4-fold higher in AA PCa samples as compared to Caucasian American (CA) PCa samples, underscoring the importance of KDM5B/FOXA1 in PCa disparities. However, the mechanism and contributions of KDM5B to prostate tumorigenesis remain elusive. We recently demonstrated that KDM5B is noticeably increased in prostate tumors of Pten/Trp53 mutant mice, and that its levels are regulated by SKP2 and TRAF6 through ubiquitination. Our preliminary data reveal that KDM5B is higher in AA PCa samples than in CA PCa samples. In addition, PTEN loss results in an increase of KDM5B in mice, and KDM5B knockout (KO) decreased the levels of FOXA1 and AR in PCa cells.
In aim 1 of this proposal, we will investigate the role of KDM5B in PTEN-null driven prostate tumorigenesis. With application of genetically-engineered mouse models, we will generate Pten/Kdm5b double mutants from Pten and Kdm5b mice, and define the effects of Kdm5b deficiency on the suppression of tumor progression in Pten-null mice.
In aim 2, we will investigate the molecular mechanisms of KDM5B signaling network in prostate cancer. We will define KDM5B target gene by ChIP assay, KDM5B ubiquitination and mutation, its regulation by PTEN-AKT, SKP2 and TRAF6, and the relevance of KDM5B modification on EZH2, FOXA1, and AR signaling pathways using human PCa cell lines (PC3, LNCaP, C4-2B, and MDA PCa 2b).
In aim 3, we will assess the effects of KDM5B inhibition on PCa growth of C4-2B and MDA PCa 2b cells, and its implications on PCa disparities. We will evaluate the impact of KDM5B KO and inhibition with compounds on the suppression of prostate tumor growth in xenografts and Luc/Pten mice. Results from this proposal should provide valuable insights into the mechanisms of epigenetic alterations in PCa, and a potential development of a novel therapeutic strategy to control PCa growth. This study should bring great benefit to all PCa patients and reduce/eliminate cancer disparities.

Public Health Relevance

The goal of this proposal is to elucidate the mechanisms on dysregulation of KDM5B in prostate cancer (PCa) and the specific contributions to the development and progression of PCa as well as PCa disparities. Results will provide significant insights into the understanding of the molecular mechanisms promoting PCa malignancy and PCa disparities, which will benefit the development of a novel and effective therapeutic strategy to reduce cancer disparities.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54MD007586-31
Application #
9449962
Study Section
Special Emphasis Panel (ZMD1)
Project Start
Project End
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
31
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Meharry Medical College
Department
Type
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Ochieng, Josiah; Nangami, Gladys; Sakwe, Amos et al. (2018) Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite-nanoparticles by tumor cells via syndecan-4. FEBS Lett 592:3274-3285
Mishra, Abheepsa; Ayasolla, Kamesh; Kumar, Vinod et al. (2018) Modulation of apolipoprotein L1-microRNA-193a axis prevents podocyte dedifferentiation in high-glucose milieu. Am J Physiol Renal Physiol 314:F832-F843
Abney, Kristopher K; Ramos-Hunter, Susan J; Romaine, Ian M et al. (2018) Selective Activation of N,N'-Diacyl Rhodamine Pro-fluorophores Paired with Releasing Enzyme, Porcine Liver Esterase (PLE). Chemistry 24:8985-8988
Ho, Meng-Hsuan; Lamont, Richard J; Chazin, Walter J et al. (2018) Characterization and development of SAPP as a specific peptidic inhibitor that targets Porphyromonas gingivalis. Mol Oral Microbiol 33:430-439
Cook, Mekeila C; Barnert, Elizabeth; Ijadi-Maghsoodi, Roya et al. (2018) Exploring Mental Health and Substance use Treatment Needs of Commercially Sexually Exploited Youth Participating in a Specialty Juvenile Court. Behav Med 44:242-249
Dash, Sabyasachi; Balasubramaniam, Muthukumar; Dash, Chandravanu et al. (2018) Biotin-based Pulldown Assay to Validate mRNA Targets of Cellular miRNAs. J Vis Exp :
Cunningham-Erves, Jennifer L; Kelly-Taylor, Kendria D; Mayo-Gamble, Tilicia L et al. (2018) A Physician's Recommendation for Human Papillomavirus Vaccination: What Makes African-American Mothers Compliant? Pediatr Infect Dis J 37:e222-e225
Cunningham-Erves, Jennifer; Forbes, Laura; Ivankova, Nataliya et al. (2018) Black mother's intention to vaccinate daughters against HPV: A mixed methods approach to identify opportunities for targeted communication. Gynecol Oncol 149:506-512
Tang, Yuyang; George, Alvin M; Petrechko, Oksana et al. (2018) Pseudotyping of HIV-1 with Human T-Lymphotropic Virus 1 (HTLV-1) Envelope Glycoprotein during HIV-1-HTLV-1 Coinfection Facilitates Direct HIV-1 Infection of Female Genital Epithelial Cells: Implications for Sexual Transmission of HIV-1. mSphere 3:
Graves, Cornelia R; Davis, Stacy F (2018) Cardiovascular Complications in Pregnancy: It Is Time for Action. Circulation 137:1213-1215

Showing the most recent 10 out of 57 publications