# Targeting KDM4B, a novel alternative splicing regulator, in castration-resistant prostate cancer (CRPC)

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $405,500

## Abstract

Alternative splicing of pre-mRNA is a fundamental mechanism to generate protein diversity that is often
deregulated in cancer cells, producing aberrant proteins that promote growth and survival. Growth of prostate
cancer (PCa) is driven by the androgen receptor (AR) activities. The standard care for metastatic PCa is
androgen-deprivation therapy (ADT). However, ADT inevitably leads to castration-resistant PCa (CRPC) that,
while still relies on the AR activities, is no longer hormone-sensitive. Among the many mechanisms underlying
CRPC, is the generation of constitutively active AR variants (AR-Vs) through alternative splicing. Of note is AR-
V7, which may play a causal role in PCa progression and treatment resistance. Until now, no FDA-approved
agent can target these AR-Vs. Recently, we identified a pro-oncogenic role for histone demethylase KDM4B in
PCa and several chemical inhibitors of KDM4B. In our preliminary studies, we found that KDM4B is necessary
and sufficient to promote AR-V7 expression. KDM4B binds RNA and interacts with many trans-acting factors
and may regulate alternative splicing of AR at both the pre-mRNA and chromatin levels. In addition, KDM4B
may have other genome-wide alternatively spliced targets that are hallmarks of cancer. High KDM4B
expression in human PCa patients predicts poor prognosis and correlates with elevated AR-V7 expression.
Based on these scientific premises, we hypothesize that KDM4B may be a gene-specific alternative splicing
regulator that dictates an oncogenic splicing pattern in CRPC and that targeting this enzyme could inhibit
CRPC and re-sensitize CRPC to current ADT. We propose three specific aims to test this hypothesis. Aim 1:
To determine the molecular mechanisms by which KDM4B regulates alternative splicing of AR-Vs. KDM4B
may promote alternative splicing by recruiting the spliceosome to the 3'-splice site of alternative exons via
binding to splicing regulatory elements (SREs) and by changing the chromatin structures around alternatively
spliced exons. We will identify these SREs and determine the chromatin landscape around alternatively spliced
exons. Aim 2. To identify KDM4B-regulated genome-wide splice variants. Preliminary studies indicated that
KDM4B may have additional alternatively spliced variants that are specific for PCa tumorigenesis. We will test
this hypothesis by comparative profiling genome-wide KDM4B-targeted splice variants, their associated SREs
and chromatin landscapes in both hormone-sensitive and refractory PCa cells. Aim 3. To generate a clinical
candidate(s) through optimization of KDM4B inhibitors. Our data indicated that the KDM4B inhibitor B3 may
serve as a strong lead compound for further optimization to generate a clinical candidate agent. We will
optimize B3 through iterative rounds of medicinal chemistry design, synthesis and testing. The notion that
KDM4B is an oncogenic regulator of alternative splicing is novel. Understanding mechanism of action of
KDM4B and identif...

## Key facts

- **NIH application ID:** 10312132
- **Project number:** 5R01CA215063-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jer-Tsong Hsieh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,500
- **Award type:** 5
- **Project period:** 2018-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312132

## Citation

> US National Institutes of Health, RePORTER application 10312132, Targeting KDM4B, a novel alternative splicing regulator, in castration-resistant prostate cancer (CRPC) (5R01CA215063-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312132. Licensed CC0.

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