KDM4B

Official Full Name

lysine demethylase 4B

Organism

Homo sapiens

GeneID

23030

Background

Enables histone H3K36 demethylase activity and histone H3K9me2/H3K9me3 demethylase activity. Predicted to be involved in brain development; chromatin remodeling; and regulation of gene expression. Located in cytosol and nucleoplasm. Implicated in autosomal dominant intellectual developmental disorder; breast cancer; colorectal cancer; malignant peripheral nerve sheath tumor; and stomach cancer. Biomarker of several diseases, including alopecia areata; lung cancer; medulloblastoma; prostate cancer; and stomach cancer. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

MRD65; JMJD2B; TDRD14B;

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Detailed Information

Recent Research

KDM4B, a jumonji- domain containing histone demethylase, is the main epigenetic regulator of mesenchymal stem cell osteogenic differentiation. KDM4B selectively demethylates H3K9me3 without affecting H3K9me2, an epigenetic marker associated with gene inhibition. KDM4B plays a key role in guiding osteoblast differentiation of mesenchymal stem cells by removing central heterochromatin H3K9me3 and activating osteoblast gene transcription. KDM4B itself is regulated by androgens, which can stimulate AR (Androgen receptor) -mediated transcription not only through demethylation activity, but also by regulating ubiquitination of prostate cancer cells. It is also overexpressed in colorectal cancer tumor tissues and colorectal cancer cell lines, and the high expression of KDM4B is positively correlated with the cell tolerance to gamma rays.

KDM4B is a critical role in the epigenetic regulation of TGF-β-mediated chondrogenic differentiation of MSCs. TGF-β is known to induce chondrogenesis by activating SMAD (intracellular proteins) signaling pathway and upregulating chondrogenic genes such as SOX9 (transcription factor SOX-9). TGF-β dramatically induced the expression of KDM4B in MSCs. Chondrogenic differentiation was significantly enhanced when KDM4B was overexpressed, and the loss of KDM4B by shRNA resulted in a significant decrease in chondrogenic potential. Mechanistically, upon TGF-β stimulation, KDM4B was recruited to the SOX9 promoter, removed the silencing H3K9me3 marks, and activated the transcription of SOX9.

KDM4B also plays an important role in regulating genes related to tumorigenesis and development. The function of n-myc (a protein with a basic helical-loop-helical domain) in the regulation of RNA metabolism seems to be unaffected by KDM4B, which indicates the specificity of KDM4B function. Inhibition of KDM4B mainly inhibits Myc function, inhibits proliferation of neuroblastoma cells, induces cell differentiation, and delays tumor growth. DNA binding by N-Myc is associated with KDM4B, with which it physically interacts, thereby maintaining low levels of repressive H3K9me2/me3 marks from chromatin loci of Myc targets such as miR17–92. The deletion of KDM4B resulted in the elevation of H3K9me3/me2 marker at the n-myc binding site, suggesting transcriptional inhibition. KDM4B synergizes with these epigenetic modifiers to enhance Myc function. Crystal structure studies showed that KDM4A catalyzed H3K9me3 and H3K36me3 substrates to have different conformations.

KDM4B is required for optimal DNA damage response. Silencing of KDM4B inhibits the activity of STAT3 (signal transducers and transcriptional activators 3), leading to the accumulation of spontaneous DSBs (DNA double-strand breaks) and reducing the ability to repair damaged DNA. CREB (a member of the CREB/ATF family of nuclear transcription factors) binds directly to the KDM4B promoter and plays an important role in promoting KDM4B expression. Therefore, overexpression of KDM4B in CRC may lead to failure of radiotherapy and other dsb-induced chemotherapy drugs. CREB plays an important role in regulating the expression of KDM4B in CRC cells. Molecular chaperone Hsp90 plays a key role in stabilizing KDM4B protein by inhibiting ubiquitin-dependent proteasome degradation, suggesting that the abundance and activity of this demethylase are regulated by different mechanisms.

KDM4B histone demethylase regulates the expression of myogenic regulators such as MyoD (a protein that plays a major role in regulating muscle differentiation), thus controlling the myogenic differentiation of C2C12 (An immortal mouse myoblast cell line) myoblasts. KDM4B histone demethylase regulates expression of myogenic regulators such as MyoD and thereby controls myogenic differentiation of C2C12 myoblast cells. KDM4B expression gradually increased during myoblast differentiation, and the depletion of KDM4B by shRNA inhibited the differentiation of C2C12 myoblasts, which was related to the decreased expression of MyoD and myogen. KDM4B shRNA inhibited the expression of luciferase reporter gene driven by MyoD promoter, and exogenously expressed MyoD saved the myoblast potential of KDM4B depleted myoblasts. KDM4B interacts with MyoD, binds MyoD and myogen promoter in vivo, and finally participates in the demethylation of MyoD and myogen promoter by trimethylation h3-k9.

Many studies have demonstrated that histone demethylase in Jumonji-domain regulates the cell processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC (Ovarian cancer). The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

References:

Castellini L , et al. KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Research, 2017:gkw1281.
Li S , et al. KDM4B promotes epithelial-mesenchymal transition through up-regulation of ZEB1 in pancreatic cancer. Acta Biochimica et Biophysica Sinica, 2015:gmv107.
Wilson C , et al. The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene, 2016.
Qiu M T , et al. KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1. Oncotarget, 2015, 6(31):31702-31720.
Choi J H , et al. The histone demethylase KDM4B interacts with MyoD to regulate myogenic differentiation in C2C12 myoblast cells. Biochemical and Biophysical Research Communications, 2015, 456(4):872-878.
Janknecht, et al. Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase. International Journal of Oncology, 2014.

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