# Mechanism and oncogenic role of lysine demethylase KDM5B in prostate cancer

> **NIH NIH U54** · MEHARRY MEDICAL COLLEGE · 2020 · $282,703

## Abstract

Abstract 
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-β, 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. ...

## Key facts

- **NIH application ID:** 9974582
- **Project number:** 5U54MD007586-34
- **Recipient organization:** MEHARRY MEDICAL COLLEGE
- **Principal Investigator:** Zhenbang Chen
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $282,703
- **Award type:** 5
- **Project period:** 1997-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974582

## Citation

> US National Institutes of Health, RePORTER application 9974582, Mechanism and oncogenic role of lysine demethylase KDM5B in prostate cancer (5U54MD007586-34). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974582. Licensed CC0.

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