Kdm3a, also known as lysine-specific histone demethylase 3A, is an H3K9me2/me1 histone demethylase in the KDM3 subfamily. It contains a catalytic Jumonji C domain and is involved in promoting gene expression. Kdm3a is associated with multiple biological pathways such as mitochondrial biogenesis, stress response, cell-cycle regulation, and Wnt/β -catenin signaling pathway, playing a crucial role in normal physiological processes and disease development [1].

In gastric cancer, Kdm3A ablation activates endogenous retrovirus expression, stimulates antitumor immunity by reconfiguring the dsRNA-MAVS-IFN axis, reshaping the tumor microenvironment, and enhancing the efficacy of anti-PD1 therapy [2]. In colorectal cancer, its expression is significantly higher in patients compared to controls, suggesting it could be a novel non-invasive blood-based biomarker [3]. In osteosarcoma, knockdown of Kdm3A weakens cell growth, metastasis, and suppresses aerobic glycolysis, as it promotes PFKFB4 transcription via the KDM3A-SP1 axis [4]. In postnatal hippocampal neurogenesis, conventional or conditional knockout of Kdm3a in neural stem/progenitor cells hinders neurogenesis, affecting learning, memory, and brain injury repair in mice, as Kdm3a regulates the Wnt/β-catenin signaling pathway [5].

In conclusion, Kdm3a is a key regulator in multiple biological processes. Its gene knockout or conditional knockout in mouse models has revealed its important roles in cancer development, including gastric, colorectal, and osteosarcoma, as well as in hippocampal neurogenesis. These findings provide potential therapeutic targets for related diseases and new insights into the underlying molecular mechanisms.

References:

1. Yoo, Jung, Jeon, Yu Hyun, Cho, Ha Young, Lee, Dong Hoon, Kwon, So Hee. 2020. Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target. In Cancers, 12, . doi:10.3390/cancers12051098. https://pubmed.ncbi.nlm.nih.gov/32354028/

2. Zheng, Jiabin, Feng, Huolun, Lin, Jiatong, Xing, Fan, Li, Yong. 2024. KDM3A Ablation Activates Endogenous Retrovirus Expression to Stimulate Antitumor Immunity in Gastric Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2309983. doi:10.1002/advs.202309983. https://pubmed.ncbi.nlm.nih.gov/39031630/

3. Polat, D, Onur, E, Yılmaz, N, Sökücü, M, Gerçeker, O F. 2023. KDM3A, a Novel Blood-Based Biomarker in Colorectal Carcinogenesis. In Balkan journal of medical genetics : BJMG, 25, 23-27. doi:10.2478/bjmg-2022-0021. https://pubmed.ncbi.nlm.nih.gov/37265967/

4. Wang, Wei, Wang, Bin. 2022. KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development. In BMC cancer, 22, 562. doi:10.1186/s12885-022-09636-8. https://pubmed.ncbi.nlm.nih.gov/35590288/

5. U, Kin Pong, Gao, Lin, Zhang, Huan, Li, Gang, Jiang, Xiaohua. 2025. KDM3A controls postnatal hippocampal neurogenesis via dual regulation of the Wnt/β-catenin signaling pathway. In Cell death and differentiation, , . doi:10.1038/s41418-025-01470-2. https://pubmed.ncbi.nlm.nih.gov/40033066/