Ehmt2-KO Mouse

Ehmt2, also known as euchromatic histone lysine methyltransferase 2 or G9a, is a SET domain-containing histone lysine methyltransferase. It is mainly responsible for histone H3 lysine 9 (H3K9) mono-and di-methylation, influencing gene expression involved in embryonic development, tissue differentiation and many cellular processes such as transcriptional regulation, genome methylation, and DNA repair [3,4,6].

In cancer research, Ehmt2 has emerged as a significant player. In microsatellite stability (MSS) colorectal cancer, its inhibition transforms the immunosuppressive microenvironment into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation. This is accompanied by galectin-7 up-regulation, which converts a "cold" tumor environment into a T-cell-inflamed one [1]. In non-small cell lung cancer, Ehmt2-mediated transcriptional reprogramming drives neuroendocrine transformation, increasing methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/β-catenin pathway. Suppression of Ehmt2 with selective inhibitors restores the sensitivity of neuroendocrine transformation cell lines to erlotinib [2]. In uveal melanoma, Ehmt2 promotes tumorigenesis via the ARHGAP29-mediated RhoA pathway, and inhibition of Ehmt2 reduces cancer cell proliferation and migration [5].

In conclusion, Ehmt2 is essential for normal development and is involved in multiple cellular processes through its histone methylation function. In disease, especially in various cancers, research on Ehmt2 using different models has revealed its significant role in tumor progression and response to therapy, suggesting it could be a potential therapeutic target in these disease areas.

References:

1. Sun, Lei, Liu, Ruonian, Wu, Zong-Jian, Kuang, Dong-Ming, Wan, Guohui. 2023. Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer. In Gastroenterology, 166, 466-482. doi:10.1053/j.gastro.2023.11.294. https://pubmed.ncbi.nlm.nih.gov/38065340/

2. Yang, Cheng, Ma, Shuxiang, Zhang, Jie, Wang, Qiming, Wang, Lihui. 2024. EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2317790121. doi:10.1073/pnas.2317790121. https://pubmed.ncbi.nlm.nih.gov/38814866/

3. Nachiyappan, Alamelu, Gupta, Neelima, Taneja, Reshma. 2022. EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms. In The FEBS journal, 289, 1329-1351. doi:10.1111/febs.16334. https://pubmed.ncbi.nlm.nih.gov/34954891/

4. Souza, Barbara Kunzler, Freire, Natalia Hogetop, Jaeger, Mariane, Brunetto, André T, Roesler, Rafael. 2021. EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors. In International journal of molecular sciences, 22, . doi:10.3390/ijms222011292. https://pubmed.ncbi.nlm.nih.gov/34681949/

5. Li, Yongyun, Zhu, Tianyu, Yang, Jie, Zhang, Jianming, Fan, Xianqun. 2023. EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway. In Acta pharmaceutica Sinica. B, 14, 1187-1203. doi:10.1016/j.apsb.2023.12.002. https://pubmed.ncbi.nlm.nih.gov/38486999/

6. Jan, Suraya, Dar, Mohd Ishaq, Wani, Rubiada, Lateef, Sammar, Syed, Sajad Hussain. 2020. Targeting EHMT2/ G9a for cancer therapy: Progress and perspective. In European journal of pharmacology, 893, 173827. doi:10.1016/j.ejphar.2020.173827. https://pubmed.ncbi.nlm.nih.gov/33347828/