Dgkg-KO Mouse

Dgkg, encoding diacylglycerol kinase gamma, is a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways [7]. Diacylglycerol kinases play dual roles in cell transformation and immunosurveillance [4].

In hepatocellular carcinoma (HCC), hypoxia-induced endothelial cell-specific Dgkg hyper-expression promotes angiogenesis and immune evasion via the ZEB2/TGF-β1 axis. Inhibition of endothelial Dgkg can enhance the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, suggesting it as a potential therapeutic target for HCC [1]. In Wagyu cattle, a homozygous missense variant in Dgkg is associated with hepatic fibrinogen storage disease, adding Dgkg to the list of candidate genes for this disorder in other species [2]. In an epileptic patient, a heterozygous mutation in Dgkg led to the generation of an induced pluripotent stem cell line, which can be used to study the pathogenic mechanisms of epilepsy and for drug development [3]. In acute myeloid leukemia (AML), high Dgkg expression is associated with a more favorable prognosis according to the TGCA database [4]. In colorectal cancer, Dgkg is hypermethylated and its expression is suppressed. Ectopic expression of wild-type and mutant forms of Dgkgγ can inhibit cell migration, invasion and Rac1 activity, suggesting a potential tumor-suppressor role [5]. In cortical GABAergic interneurons, Dgkg is dominantly expressed in somatostatin-expressing cells and affects neurite outgrowth [6]. In glioblastoma, a hypoxia-induced alternatively spliced transcript Dgkg-Δ exon13 promotes tumor proliferation and infiltration [8].

In summary, Dgkg is involved in multiple biological processes and diseases. Its role in tumor angiogenesis, immune evasion, and as a potential tumor suppressor, along with its association with genetic disorders like hepatic fibrinogen storage disease and epilepsy, highlights its importance. Functional studies, especially those using in vivo models, have provided insights into its complex functions in different disease conditions, offering potential directions for therapeutic development.

References:

1. Zhang, Liren, Xu, Jiali, Zhou, Suiqing, Li, Qing, Wang, Xuehao. 2023. Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma. In Journal of hepatology, 80, 82-98. doi:10.1016/j.jhep.2023.10.006. https://pubmed.ncbi.nlm.nih.gov/37838036/

2. Jacinto, Joana G P, Wohlsein, Peter, Häfliger, Irene M, Grünberg, Walter, Drögemüller, Cord. 2023. A missense variant in DGKG as a recessive functional variant for hepatic fibrinogen storage disease in Wagyu cattle. In Journal of veterinary internal medicine, 37, 2631-2637. doi:10.1111/jvim.16865. https://pubmed.ncbi.nlm.nih.gov/37681469/

3. Liu, Ya-Qing, Ling, Tiao-Wen, Wang, Hong-Yan, Song, Wen-Jun, Wang, Tian-Cheng. 2022. Generation of an integration-free induced pluripotent stem cell line (LZUSHI001-A) from an epileptic patient with DGKG mutation. In Stem cell research, 61, 102768. doi:10.1016/j.scr.2022.102768. https://pubmed.ncbi.nlm.nih.gov/35421845/

4. Gravina, Teresa, Boggio, Chiara Maria Teresa, Gorla, Elisa, Corà, Davide, Baldanzi, Gianluca. 2023. Role of Diacylglycerol Kinases in Acute Myeloid Leukemia. In Biomedicines, 11, . doi:10.3390/biomedicines11071877. https://pubmed.ncbi.nlm.nih.gov/37509516/

5. Kai, Masahiro, Yamamoto, Eiichiro, Sato, Akiko, Toyota, Minoru, Suzuki, Hiromu. 2017. Epigenetic silencing of diacylglycerol kinase gamma in colorectal cancer. In Molecular carcinogenesis, 56, 1743-1752. doi:10.1002/mc.22631. https://pubmed.ncbi.nlm.nih.gov/28218473/

6. Fukumoto, Keita, Tamada, Kota, Toya, Tsuyoshi, Yanagawa, Yuchio, Takumi, Toru. 2017. Identification of genes regulating GABAergic interneuron maturation. In Neuroscience research, 134, 18-29. doi:10.1016/j.neures.2017.11.010. https://pubmed.ncbi.nlm.nih.gov/29203264/

7. Taniguchi-Ponciano, Keiko, Hinojosa-Alvarez, Silvia, Hernandez-Perez, Jesus, Marrero-Rodriguez, Daniel, Mercado, Moises. 2024. Longitudinal multiomics analysis of aggressive pituitary neuroendocrine tumors: comparing primary and recurrent tumors from the same patient, reveals genomic stability and heterogeneous transcriptomic profiles with alterations in metabolic pathways. In Acta neuropathologica communications, 12, 142. doi:10.1186/s40478-024-01796-x. https://pubmed.ncbi.nlm.nih.gov/39217365/

8. Yang, Ming, Chu, Liangzhao, Lin, Shukai, Han, Feng, Liu, Jian. 2025. The alternatively spliced diacylglycerol kinase gamma-Δ exon13 transcript generated under hypoxia promotes glioblastoma progression. In Oncology research, 33, 1189-1198. doi:10.32604/or.2024.055102. https://pubmed.ncbi.nlm.nih.gov/40296900/