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Last update 23 Jan 2025

KDM4B

Last update 23 Jan 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

254

Literatures (Medical) associated with KDM4B

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.

01 Dec 2024·Molecular Biology Reports

Genotype–phenotype correlation study of structural abnormalities in a fetal brain caused by a novel KDM4B variant

Article

Author: Jia, Jian-An ; Zhao, Xuliang ; Li, Xu ; Yu, Min ; Tian, Ruixia ; Zhu, Fuxi

BACKGROUNDFetal ventriculomegaly (VM), a common brain structure malformation detected during prenatal ultrasound diagnosis, is associated with an increased risk of neurodevelopmental disorders (NDDs) after birth. KDM4B encodes a lysine-specific demethylase that interacts with histone H3K23me3. Variations in KDM4B are reportedly associated with human NDDs; however, only 11 such patients have been reported. Herein, we report a fetus with VM and agenesis of the corpus callosum (ACC), which suggests that KDM4B plays an important role in fetal brain development.METHODSFetal skin tissue and parental peripheral venous blood samples were collected. Whole-exome and Sanger sequencing were performed to analyze fetal germline variants. Human 293T cells transfected with wild-type or mutant KDM4B were used for western blotting (WB) to analyze protein expression levels.RESULTSAn insertion variant of KDM4B, NM_015015.3: c.2889_2890insGAGAGCATCACGGTGAGCTGTGGGGTGGGGCAGGGGGCGGGGGGAGGCTGGGAGCACAGTGACAACCTGTACCCC, was identified in the fetal tissue; however, the parents carried the wild-type gene. The WB results indicated significantly reduced expression of the mutant protein, likely owing to decreased stability.CONCLUSIONSThe structural abnormalities in the brain of the studied fetus may be attributed to an insertion variant of KDM4B. This study highlights the importance of screening for KDM4B variants and considering potential copy number variations when observing VM or ACC in prenatal ultrasound imaging.

01 Nov 2024·Journal of Dental Research

Fumarate Restrains Alveolar Bone Restoration via Regulating H3K9 Methylation

Article

Author: Ye, H.Y. ; He, Y.Y. ; Xiang, J. ; Zhang, H.M. ; Zhang, Y.Y. ; Ji, P. ; Bai, H.L. ; Xu, L. ; Zhai, Q.M. ; Liu, W.Z. ; Liu, X. ; Zhang, H. ; Cannon, R.D.

Nonresolving inflammation causes irreversible damage to periodontal ligament stem cells (PDLSCs) and impedes alveolar bone restoration. The impaired tissue regeneration ability of stem cells is associated with abnormal mitochondrial metabolism. However, the impact of specific metabolic alterations on the differentiation process of PDLSCs remains to be understood. In this study, we found that inflammation altered the metabolic flux of the tricarboxylic acid cycle and induced the accumulation of fumarate through metabolic testing and metabolic flux analysis. Transcriptome sequencing revealed the potential of fumarate in modulating epigenetics. Specifically, histone methylation typically suppresses the expression of genes related to osteogenesis. Fumarate was found to impede the osteogenic differentiation of PDLSCs that exhibited high levels of H3K9me3. Various techniques, including assay for transposase-accessible chromatin with high-throughput sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing, were used to identify the target genes regulated by H3K9me3. Mechanistically, accumulated fumarate inhibited lysine-specific demethylase 4B (KDM4B) activity and increased H3K9 methylation, thus silencing asporin gene transcription. Preventing fumarate from binding to the histone demethylase KDM4B with α-ketoglutarate effectively restored the impaired osteogenic capacity of PDLSCs and improved alveolar bone recovery. Collectively, our research has revealed the significant impact of accumulated fumarate on the regulation of osteogenesis in stem cells, suggesting that inhibiting fumarate production could be a viable therapeutic approach for treating periodontal diseases.

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