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Last update 08 May 2025

KDM4B

Last update 08 May 2025

Basic Info

Synonyms

[histone H3]-trimethyl-L-lysine(9) demethylase 4B, JHDM3B, JmjC domain-containing histone demethylation protein 3B

+ [10]

Introduction

Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Only able to demethylate trimethylated H3 'Lys-9', with a weaker activity than KDM4A, KDM4C and KDM4D. Demethylation of Lys residue generates formaldehyde and succinate (PubMed:16603238, PubMed:28262558). Plays a critical role in the development of the central nervous system (CNS).

Drugs associated with KDM4B

Zavondemstat

Target

KDM4B

Mechanism

KDM4B inhibitors

Active Org.

Tachyon Therapeutics, Inc.

Originator Org.

Tachyon Therapeutics, Inc.

Active Indication

Advanced cancer [+2]

Inactive Indication

Hematologic Neoplasms

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SS-34

Target

KDM4B

Mechanism

KDM4B inhibitors

Active Org.-

Originator Org.

The University of Texas System

Active Indication-

Inactive Indication

Castration-Resistant Prostatic Cancer

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with KDM4B

NCT05076552

/ Active, not recruitingPhase 1

A Phase 1a/1b Open-label Study to Assess the Safety, Pharmacokinetics, and Antitumor Activity of Oral TACH101 in Patients With Advanced or Metastatic Solid Tumors

The main objective for part 1a of the study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of oral TACH101 in participants with advanced and metastatic solid tumors. For part 1b, the main objective is the objective response rate (ORR) as assessed by radiographic progression measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Start Date17 Feb 2023

Sponsor / Collaborator

Tachyon Therapeutics, Inc.

100 Clinical Results associated with KDM4B

100 Translational Medicine associated with KDM4B

0 Patents (Medical) associated with KDM4B

251

Literatures (Medical) associated with KDM4B

01 Jun 2025·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Role and regulatory mechanism of DLX5 in rhabdomyosarcoma tumorigenesis

Article

Author: Zheng, Jun ; Zhang, Chaoji ; Gao, Quanli ; Wu, Zining ; Liu, Xinpei ; Ma, Guotao ; Zhao, Yanxue

Rhabdomyosarcoma (RMS), a common malignant tumor in children, presents numerous challenges in clinical treatment. This study investigated the specific functions and regulatory mechanisms of distal-less homeobox 5 (DLX5) in RMS. Data from TCGA, GEO and GEPIA databases were downloaded and analyzed. The effect of DLX5 and PAX3-FOXO1 on RMS cells was examined through cellular experiments. Binding activity between DLX5 and H3K9me2 was assessed using pull-down and chromatin immunoprecipitation-qPCR assays. Additionally, RMS model mice were constructed via xenotransplantation to validate the in vivo effects of DLX5 on RMS. The results revealed that DLX5 was upregulated in RMS tissues and increased in various RMS cell lines, particularly in alveolar RMS cell lines. DLX5 knockdown inhibited malignant biological behaviors. Besides, DLX5 expression was associated with myogenic differentiation of RMS cells. While the overexpression or knockdown of DLX5 did not affect PAX-FOXO1 expression. PAX3-FOXO1 knockdown reduced DLX5 expression, indicating that DLX5 act as a downstream effector of PAX3-FOXO1. Mechanistically, PAX3-FOXO1 regulated DLX5 expression through KDM4B/H3K9me2 axis. In vitro experiments further demonstrated that knockout of DLX5 or KDM4B inhibited tumor growth. In conclusion, DLX5 expression was increased in PAX3-FOXO1-driven RMS, and its knockdown inhibited malignant biological behaviors of RMS cells. Moreover, the aberrant expression of DLX5 in PAX3-FOXO1-driven RMS was regulated by KDM4B/H3K9me2 axis. These findings provided potential therapeutic targets for RMS treatment.

01 Apr 2025·The American Journal of Human Genetics

FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature

Article

Author: Faqeih, Eissa Ali ; Shin, Jay W ; El Bejjani, Mireille ; Bertoli-Avella, Aida M ; Khan, Suliman ; Al-Maawali, Almundher ; Al Shamsi, Aisha ; Jain, Ruchi ; Alghamdi, Malak ; Shenbagam, Shruti ; Ali, Fahad R ; Perrin, Arnaud ; Alkuraya, Fowzan S ; Alfadhel, Majid ; Almontashiri, Naif A M ; Al-Shidhani, Azza ; El-Hattab, Ayman W ; ElGhazali, Gehad ; Tfayli, Hala ; Said Al-Kindi, Said Ahmed ; Abu Subieh, Hala ; Al Saman, Abdulaziz ; Ordoñez, Natalia ; Altunoğlu, Umut ; Khalifeh, Simone ; Taylor, Alan ; Al Ojaimi, Mode ; Abou Tayoun, Ahmad ; Al-Futaisi, Amna ; Almarri, Mohamed A ; Ramachandran, Revathy ; Alhashmi, Nadia ; Mori, Mari ; Reversade, Bruno ; Jacob, Anju ; Mohamad Sahari, Umar Bin ; Johmura, Yoshikazu ; Bauer, Peter ; Alsheikh-Ali, Alawi ; Rabea, Fatma ; Ramakrishna, Navin B ; Arabi, Mariam ; Ali, Nur Ain ; Thalange, Nandu ; Alhabshan, Fahad ; Ferreira, Mariana ; Pinto Basto, Jorge ; Nakanishi, Makoto ; Ohta, Tomohiko ; Sinha, Shruti ; Chekroun, Ikram

FBXO22 encodes an F-box protein, which acts as a substrate-recognition component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex. Despite its known roles in the post-translational ubiquitination and degradation of specific substrates, including histone demethylases, the impact of FBXO22 on human development remains unknown. Here, we characterize a pleiotropic syndrome with prominent prenatal onset growth restriction and notable neurodevelopmental delay across 16 cases from 14 families. Through exome and genome sequencing, we identify four distinct homozygous FBXO22 variants with loss-of-function effects segregating with the disease: three predicted to lead to premature translation termination due to frameshift effects and a single-amino-acid-deletion variant, which, we show, impacts protein stability in vitro. We confirm that affected primary fibroblasts with a frameshift mutation are bereft of endogenous FBXO22 and show increased levels of the known substrate histone H3K9 demethylase KDM4B. Accordingly, we delineate a unique epigenetic signature for this disease in peripheral blood via long-read sequencing. Altogether, we identify and demonstrate that FBXO22 deficiency leads to a pleiotropic syndrome in humans, encompassing growth restriction and neurodevelopmental delay, the pathogenesis of which may be explained by broad chromatin alterations.

01 Jan 2025·Journal of Cellular Biochemistry

KDM4B Histone Demethylase Inhibition Attenuates Tumorigenicity of Malignant Melanoma Cells by Overriding the p53‐Mediated Tumor Suppressor Pathway

Article

Author: Nagase, Yukako ; Hirata, Sho ; Kondo, Yukiko ; Serada, Satoshi ; Obara, Mami ; Hasan, Arif Ul ; Sato, Sachiko ; Taira, Eiichi

ABSTRACTDespite significant advances in the treatment of cutaneous melanoma (hereafter melanoma), the prognosis remains less favorable due to therapeutic resistance, which is presumably linked to epigenetic dysregulation. We hypothesized that the histone lysine demethylase KDM4B could play a pivotal role in controlling therapy‐resistant melanoma. To validate our hypothesis, we retrieved RNA sequencing data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) program and observed upregulation of KDM4B in both primary and metastatic melanoma, which was associated with poor survival. To explore its role, we used murine B16, human SK‐MEL‐5, and G‐361 melanoma cells as in vitro models of melanoma. We found that KDM4B inhibition using NCGC00244536 increased global levels of H3K9me3 and downregulated the expressions of cell cycle progression–related genes Cdk1, Cdk4, Ccnb1, and Ccnd1. Moreover, genetic ablation of KDM4B or its chemical inhibition using NCGC00244536 reduced p53 production by upregulating MDM2, which enhances the proteolytic degradation of p53. Interestingly, despite the reduction of p53, these interventions augmented apoptosis and senescence‐induced cell death by activating pathways downstream of p53, as evidenced by reduced levels of pro‐survival Bcl‐2 and Bcl‐xL proteins and increased production of pro‐apoptotic cleaved caspase‐3, caspase‐7, Bax, and the senescence inducer Cdkn1a. Compared to the FDA‐approved anti‐melanoma agent dacarbazine, NCGC00244536 exhibited more pronounced cytotoxic and antiproliferative effects in melanoma cells. Importantly, NCGC00244536 demonstrated minimal cytotoxicity to low Kdm4b‐expressing mouse embryonic fibroblasts. In conclusion, our findings suggest that KDM4B inhibition can override the antitumor effect of p53, and potentially serve as a therapeutic strategy for melanoma.

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KDM4B

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