# Molecular and Epigenetic Control of Wnt/b-catenin-mediated oncogenesis by KDM4B

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $428,535

## Abstract

Project Summary/Abstract
 Abnormal Wnt/β-catenin signaling is associated with various types of human cancers, most notably
colorectal cancers (CRCs) due to APC and CTNNB1 (β-catenin) mutations. CRCs are the third most common
cancer worldwide and the fourth most common cause of death. Wnt/β-catenin signaling exhibits its oncogenic
activities by inducing the expression of Wnt target genes such as CCND1 (Cyclin D1) and MYC (c-Myc) through
β-catenin/T cell factor (Tcf)-mediated transcription. Although APC and CTNNB1 mutations play a critical role in
human CRC initiation and development, emerging evidence suggests that epigenetic modifications act
synergistically in human CRC initiation and development. A small subset of cancer stem cells (CSCs) or cancer
initiating cells with the ability to self-renew and maintain the tumor has been isolated from human CRCs. We and
others have found that β-catenin/Tcf-mediated transcription is hyperactivated in human colorectal CSCs
compared to non-CSC tumor cells. In this application, we identified that lysine-specific demethylase 4B (KDM4B)
that erases H3K9me3 marks was highly expressed in human CRCs. The knockdown or pharmacological
inhibition of KDM4B in human CRC cells significantly inhibited the expression of Wnt target genes. To explore
the functional roles of KDM4B in vivo, we generated Kdm4bflox/flox (Kdm4bf/f) mice that carry conditional Kdm4b
alleles. Although the deletion of Kdm4b in mice causes intestinal abnormalities and reduced crypt stem cells,
unlike the deletion of β-catenin, we found that mice can tolerate KDM4B deficiency, indicating that targeting
KDM4B might provide a safe therapeutic window for the treatment of human CRCs. Consistently, we found that
the intestinal deletion of Kdm4b completely inhibited intestinal tumorigenesis in ApcMin/+ mice which develop
multiple adenomas in the small intestine due to increased β-catenin/Tcf-mediated transcription. Additionally, we
found that KDM4B interacts with the intestinal stem cell transcription factor ASCL2 which serve as a positive
feedback to enhance β-catenin/Tcf-mediated transcription. Based on these exciting discoveries, we hypothesize
that KDM4B might epigenetically control Wnt/β-catenin-mediated oncogenesis and is required for the
tumorigenic potentials of human colorectal CSCs. Using molecular, cellular, genetic and epigenetic approaches,
we will determine: 1) Whether the knockout or pharmacological inhibition of KDM4B inhibits CRC tumorigenesis
in vivo; 2) Whether KDM4B epigenetically controls tumorigenic potentials and self-renewal of CSCs in human
CRCs; 3) How KDM4B epigenetically controls Wnt/β-catenin-mediated transcription and tumorigenesis by
erasing H3K9me3. Since histone demethylases are enzymes which can be readily targeted by small molecules
inhibitors, novel findings from our studies may lead to develop novel strategies for the treatment of human CRCs
and other cancers.

## Key facts

- **NIH application ID:** 9892322
- **Project number:** 1R01CA236878-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CUN-YU WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,535
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892322

## Citation

> US National Institutes of Health, RePORTER application 9892322, Molecular and Epigenetic Control of Wnt/b-catenin-mediated oncogenesis by KDM4B (1R01CA236878-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892322. Licensed CC0.

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