Kdm4b, a member of the KDM4 family of Jumonj domain histone demethylases, specifically targets di-and tri-methylated lysine 9 on histone H3 (H3K9me3). By removing this modification, it plays a central role in regulating nuclear processes such as gene transcription, DNA replication, and DNA repair, and is involved in cancer progression and normal developmental processes [1,4,5].

In skeletal aging, loss of Kdm4b in mesenchymal stromal cells (MSCs) exacerbates skeletal aging and osteoporosis, reducing bone formation and increasing marrow adiposity via increasing H3K9me3. It also impairs MSC self-renewal and promotes exhaustion by inducing senescence-associated heterochromatin foci formation [2]. In oral bone aging, loss of Kdm4b in oral mesenchymal stem cells (OMSCs) inhibits osteogenesis, promotes adipogenesis and OMSC senescence, impairing bone-fat balance in the mandible [7]. In mice, disruption of Kdm4b leads to reduced total brain volume, decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly, and in humans, heterozygous variants in Kdm4b are associated with global developmental delay and neuroanatomical defects [3]. In glioblastoma, silencing Kdm4b inhibits cell survival, proliferation, migration, and invasion, downregulating the oncoprotein MYC and suppressing related proteins [6]. In prostate cancer, upregulated Kdm4b promotes cell proliferation by activating autophagy [8]. In uterine corpus endometrial carcinoma, Kdm4b is overexpressed, associated with poor prognosis, and is related to immune cell infiltration and immune checkpoint molecules [9].

In conclusion, Kdm4b plays crucial roles in multiple biological processes and diseases. Gene knockout (KO) and conditional knockout (CKO) mouse models have been instrumental in revealing its functions in skeletal and oral bone aging, brain development, and cancer progression. These findings enhance our understanding of disease mechanisms and suggest Kdm4b as a potential therapeutic target in various disease areas.

References:

1. Wilson, Cailin, Krieg, Adam J. 2019. KDM4B: A Nail for Every Hammer? In Genes, 10, . doi:10.3390/genes10020134. https://pubmed.ncbi.nlm.nih.gov/30759871/

2. Deng, Peng, Yuan, Quan, Cheng, Yingduan, Yu, Bo, Wang, Cun-Yu. 2021. Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging. In Cell stem cell, 28, 1057-1073.e7. doi:10.1016/j.stem.2021.01.010. https://pubmed.ncbi.nlm.nih.gov/33571444/

3. Duncan, Anna R, Vitobello, Antonio, Collins, Stephan C, Yalcin, Binnaz, Agrawal, Pankaj B. 2020. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects. In American journal of human genetics, 107, 1170-1177. doi:10.1016/j.ajhg.2020.11.001. https://pubmed.ncbi.nlm.nih.gov/33232677/

4. Ni, Fangjing, Tang, Heting, Cheng, Siteng, Zhang, Encheng, Wang, Xiang. 2023. KDM4B: A promising oncology therapeutic target. In Cancer science, 115, 8-16. doi:10.1111/cas.16005. https://pubmed.ncbi.nlm.nih.gov/37923555/

5. Wang, Zhongze, Cai, Huarui, Zhao, Erhu, Cui, Hongjuan. 2022. The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression. In Frontiers in cell and developmental biology, 9, 790129. doi:10.3389/fcell.2021.790129. https://pubmed.ncbi.nlm.nih.gov/35186950/

6. Wang, Zhongze, Cai, Huarui, Li, Zekun, Zhao, Erhu, Cui, Hongjuan. 2023. Histone demethylase KDM4B accelerates the progression of glioblastoma via the epigenetic regulation of MYC stability. In Clinical epigenetics, 15, 192. doi:10.1186/s13148-023-01608-4. https://pubmed.ncbi.nlm.nih.gov/38093312/

7. Deng, Peng, Chang, Insoon, Wang, Jiongke, Yu, Bo, Wang, Cun-Yu. 2022. Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging. In International journal of oral science, 14, 24. doi:10.1038/s41368-022-00175-3. https://pubmed.ncbi.nlm.nih.gov/35525910/

8. Sha, Jianjun, Han, Qing, Chi, Chenfei, Xia, Weiliang, Xue, Wei. 2019. Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy. In Journal of cellular physiology, 235, 2129-2138. doi:10.1002/jcp.29117. https://pubmed.ncbi.nlm.nih.gov/31468537/

9. Zhang, Mengjun, Liu, Yuan, Hou, Siyu, Yin, Yue, Chen, Xiuwei. 2022. KDM4B, a potential prognostic biomarker revealed by large-scale public databases and clinical samples in uterine corpus endometrial carcinoma. In Molecular omics, 18, 506-519. doi:10.1039/d1mo00287b. https://pubmed.ncbi.nlm.nih.gov/35485290/