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Last update 08 May 2025

KDM3B

Last update 08 May 2025

Basic Info

Synonyms

[histone H3]-dimethyl-L-lysine(9) demethylase 3B, C5orf7, chromosome 5 open reading frame 7

+ [12]

Introduction

Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Demethylation of Lys residue generates formaldehyde and succinate. May have tumor suppressor activity.

Drugs associated with KDM3B

P3FI-63

Target

KDM3B

Mechanism

KDM3B inhibitors

Active Org.

National Cancer Institute [+1]

Originator Org.

Leidos, Inc.

Active Indication

Rhabdomyosarcoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

P3FI-90

Target

KDM3B

Mechanism

KDM3B inhibitors

Active Org.

Leidos, Inc. [+1]

Originator Org.

Leidos, Inc.

Active Indication

Rhabdomyosarcoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

KA-7

Target

KDM3B

Mechanism

KDM3B agonists

Active Org.-

Originator Org.-

Active Indication-

Inactive Indication

acute leukemia

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KDM3B

100 Translational Medicine associated with KDM3B

0 Patents (Medical) associated with KDM3B

Literatures (Medical) associated with KDM3B

01 Mar 2025·Cancer Gene Therapy

Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C

Article

Author: Schwarz, Franziska Maria ; Wimberger, Pauline ; Theis, Mirko ; Link, Theresa ; Yang, Ruming ; Klotz, Daniel Martin ; Brux, Melanie ; Kuhlmann, Jan Dominik ; Buchholz, Frank ; Harb, Hani

AbstractPARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit of PARPi in patients without homologous recombination deficiency (HRD) remains an unmet clinical need. We sought to identify genetic modulators of PARPi response, guiding pharmacological PARPi sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by the small inhibitor methylstat, promote PARPi resistance. Methylstat synergistically interacted with olaparib, and (re-)sensitized ovarian cancer cells to PARPi treatment, surpassing the efficacy of common demethylase inhibitors. Genetic knockout of JMJD1B and/or JMJD1C phenocopied the effect of methylstat in an additive manner. Validation studies revealed methylstat to be a universal PARPi-sensitizing drug, effective, regardless of PARPi resistance status or BRCA1 mutational background. Methylstat modulated clonal cancer dynamics by mitigating positive selection of PARPi-resistant or BRCA1-proficient cells under olaparib treatment. Using a model of PARPi-induced cellular toxicity, we showed that methylstat impairs cellular DNA repair, indicated by an increased susceptibility of ovarian cancer cells to olaparib-induced DNA double strand breaks after methylstat exposure. This study proposes the histone demethylase inhibitor methylstat as an epigenetic drug for overcoming PARPi-resistance or for increasing efficacy of PARPi beyond HRD in ovarian cancer patients.

04 Oct 2024·Cancer Discovery

CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype-specific Vulnerability in IDH2- and TET2-mutant Cells

Article

Author: Bagish, Maya ; Wu, Xiaodi ; Wereski, Matthew ; Sango, Junya ; Park, Young C. ; Cai, Sheng F. ; Waarts, Michael R. ; Miles, Linde A. ; Csete, Isabelle ; Romero-Vega, Angelica C. ; Fernández-Maestre, Inés ; Mowla, Shoron ; Shih, Alan H. ; Butler, Jason M. ; Martinez Benitez, Anthony R. ; Eisman, Shira E. ; Bowman, Robert L. ; Boileau, Meaghan ; O’Connor, Kavi ; Koche, Richard P. ; Levine, Ross L. ; Armstrong, Scott A. ; Shan, Yufan ; Papapetrou, Eirini P. ; Xiao, Wenbin

AbstractClonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies.See related commentary by Khabusheva and Goodell, p. 1768

01 Aug 2024·iScience

Reorganization of H3K9me heterochromatin leads to neuronal impairment via the cascading destruction of the KDM3B-centered epigenomic network

Article

Author: Kim, Chul-Hong ; Jo, Ah-Ra ; An, Mi-Jin ; Seo, Sang-Beom ; Jung, Youn-Sang ; Kim, Jinho ; Park, Yuna ; Kim, Dae-Hyun ; Rhee, Sangmyung ; Kim, Jung-Woong ; Kim, Ji-Young ; Kim, Jeongkyu ; Hwangbo, Yujeong ; Shin, Geun-Seup ; Kim, Mi Jin ; Lee, Hyun-Min

Histone H3K9 methylated heterochromatin silences repetitive non-coding sequences and lineage-specific genes during development, but how tissue-specific genes escape from heterochromatin in differentiated cells is unclear. Here, we examine age-dependent transcriptomic profiling of terminally differentiated mouse retina to identify epigenetic regulators involved in heterochromatin reorganization. The single-cell RNA sequencing analysis reveals a gradual downregulation of Kdm3b in cone photoreceptors during aging. Disruption of Kdm3b (Kdm3b ^+/- ) of 12-month-old mouse retina leads to the decreasing number of cones via apoptosis, and it changes the morphology of cone ribbon synapses. Integration of the transcriptome with epigenomic analysis in Kdm3b ^+/- retinas demonstrates gains of heterochromatin features in synapse assembly and vesicle transport genes that are downregulated via the accumulation of H3K9me1/2. Contrarily, losses of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that the KDM3B-centered epigenomic network is crucial for balancing of cone photoreceptor homeostasis via the modulation of gene set-specific heterochromatin features during aging.

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KDM3B

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