Kdm5d, also known as lysine-specific demethylase 5D, is a histone demethylase. It plays a crucial role in chromatin-related processes by mediating histone demethylation, which can influence gene expression and is involved in various biological pathways, such as cell cycle regulation and signal transduction [3]. Understanding its function is essential as it is implicated in multiple diseases, highlighting its biological importance. Genetic models, especially mouse models, are valuable for studying Kdm5d's role.

In a murine CRC model (iKAP), deletion of Kdm5d in cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells, suggesting that KDM5D-mediated disruption of cancer cell adhesion and tumour immunity contributes to sex differences in KRAS* CRC [1]. In non-small cell lung cancer, KDM5D inhibits cell proliferation and migration via inactivating p38α as it demethylates p38α at K165, suppressing tumour progression [2]. In head and neck squamous cell carcinoma, KDM5D knockdown reduced the tolerance of persister cells to platinum agents and caused cell cycle deregulation, indicating its role in the development of cisplatin-tolerant persister cells [3].

In conclusion, Kdm5d is a significant histone demethylase involved in regulating cell-related functions and disease-associated processes. Studies using gene knockout or conditional knockout mouse models have revealed its role in cancer-related diseases such as colorectal, lung, and head-neck cancers, highlighting its potential as a therapeutic target for these diseases.

References:

1. Li, Jiexi, Lan, Zhengdao, Liao, Wenting, Wang, Y Alan, DePinho, Ronald A. 2023. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. In Nature, 619, 632-639. doi:10.1038/s41586-023-06254-7. https://pubmed.ncbi.nlm.nih.gov/37344599/

2. Chen, Jingying, Wang, Ting, Zhang, Dongzhe, Wang, Xin, Li, Xia. 2024. KDM5D histone demethylase mediates p38α inactivation via its enzymatic activity to inhibit cancer progression. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2402022121. doi:10.1073/pnas.2402022121. https://pubmed.ncbi.nlm.nih.gov/39636854/

3. Chen, Tsung-Ming, Huang, Chih-Ming, Setiawan, Syahru Agung, Sheen, Chih-Chi, Yeh, Chi-Tai. 2023. KDM5D Histone Demethylase Identifies Platinum-Tolerant Head and Neck Cancer Cells Vulnerable to Mitotic Catastrophe. In International journal of molecular sciences, 24, . doi:10.3390/ijms24065310. https://pubmed.ncbi.nlm.nih.gov/36982384/