Kdm4d, a lysine demethylase, is involved in regulating gene expression by demethylating H3K9me3. It plays significant roles in various biological processes and is associated with multiple pathways, contributing to the overall understanding of cell homeostasis, differentiation, and disease development. Genetic models, such as KO mouse models, have been crucial in uncovering its functions [1,3].

In Kdm4d mutant male mice, subfertility was observed due to impaired sperm motility. The absence of Kdm4d led to an altered distribution of H3K9me3 in round spermatids, indicating its role in generating motile sperm [1]. In acute myeloid leukemia (AML), knockdown of Kdm4D inhibited cell proliferation, induced cell cycle arrest and apoptosis, and high expression was correlated with poor survival, suggesting its role in promoting AML cell development [2]. In renal cancer, high KDM4D expression was associated with advanced grade and lower survival, and it was found to promote cancer progression and angiogenesis through JAG1 signaling [4]. In esophageal squamous cell carcinoma, KDM4D acts as a tumor suppressor, and its deficiency enhanced tumor growth, migration, and stemness [5].

In conclusion, Kdm4d has diverse functions in different biological processes. The gene knockout mouse models have been instrumental in revealing its role in male infertility, as well as in various cancers including AML, renal cancer, and esophageal squamous cell carcinoma. These findings provide insights into potential therapeutic targets and prognostic markers related to these disease areas.

References:

1. Xu, Zhuoran, Fujimoto, Yuka, Sakamoto, Mizuki, Ikawa, Masahito, Ishiuchi, Takashi. 2024. Kdm4d mutant mice show impaired sperm motility and subfertility. In The Journal of reproduction and development, 70, 320-326. doi:10.1262/jrd.2024-039. https://pubmed.ncbi.nlm.nih.gov/39034148/

2. Wu, Wei, Cao, Xiaonian, Mo, Luxia. 2021. Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1. In American journal of translational research, 13, 2308-2319. doi:. https://pubmed.ncbi.nlm.nih.gov/34017391/

3. Xie, Zhongyu, Che, Yunshu, Huang, Guo, Wu, Yanfeng, Shen, Huiyong. 2024. Iron-dependent KDM4D activity controls the quiescence-activity balance of MSCs via the PI3K-Akt-Foxo1 pathway. In Cellular and molecular life sciences : CMLS, 81, 360. doi:10.1007/s00018-024-05376-z. https://pubmed.ncbi.nlm.nih.gov/39158700/

4. Yan, Hao, Zhu, Liangsong, Zhang, Jin, Lin, Zongming. 2021. Histone demethylase KDM4D inhibition suppresses renal cancer progression and angiogenesis through JAG1 signaling. In Cell death discovery, 7, 284. doi:10.1038/s41420-021-00682-y. https://pubmed.ncbi.nlm.nih.gov/34667158/

5. Yao, Wenjian, Wang, Jianjun, Zhu, Li, Wu, Sen, Wei, Li. 2021. Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma. In Frontiers in oncology, 11, 761346. doi:10.3389/fonc.2021.761346. https://pubmed.ncbi.nlm.nih.gov/34820329/