Chka-KO Mouse

Chka, short for choline kinase α, is an enzyme that converts choline to phosphocholine. It is involved in the Kennedy pathways, which catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, crucial components of eukaryotic cell membranes [1].

Bi-allelic variants in CHKA were found in six individuals from five families, presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Functional testing in a yeast model determined these variants reduce CHKA's enzymatic activity, impairing the first step of the Kennedy pathway, thus suggesting CHKA as a novel autosomal-recessive gene for this neurodevelopmental disorder [1].

In cancer research, CHKA is highly expressed in lung adenocarcinoma, colorectal carcinoma, and glioma tissues, closely associated with poor prognosis in lung and colorectal cancer patients [2,5,3]. Knockdown of CHKA inhibits the proliferation, invasion and migration of glioma and colorectal cancer cells [3,5]. Also, chloroquine suppresses colorectal cancer progression by targeting CHKA to inhibit the PI3K/AKT pathway [6]. In endometrial cancer, advanced glycation end products upregulate CHKA-mediated choline metabolism, activating the PI3K/AKT pathway and enhancing the cancer cells' malignant behavior [7]. Additionally, a CHKA polymorphism (rs3794186) may correlate with serum α-fetoprotein levels in hepatocellular carcinoma [8]. In a California population, a CHKA SNP (hCV1562388) was associated with a reduced risk of spina bifida [4].

In conclusion, Chka plays essential roles in the Kennedy pathway for cell-membrane lipid synthesis. Studies on Chka, especially through loss-of-function experiments in various cell models, have revealed its significance in neurodevelopmental disorders and multiple types of cancers, as well as its potential association with spina bifida and serum α-fetoprotein levels in hepatocellular carcinoma. These findings contribute to understanding the underlying mechanisms of these diseases and may provide new targets for treatment.

References:

1. Klöckner, Chiara, Fernández-Murray, J Pedro, Tavasoli, Mahtab, McMaster, Christopher R, Platzer, Konrad. . Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly. In Brain : a journal of neurology, 145, 1916-1923. doi:10.1093/brain/awac074. https://pubmed.ncbi.nlm.nih.gov/35202461/

2. Zhang, Li, Chen, Ping, Yang, Shen, Wu, Peng, Jiang, Shujuan. 2016. CHKA mediates the poor prognosis of lung adenocarcinoma and acts as a prognostic indicator. In Oncology letters, 12, 1849-1853. doi:. https://pubmed.ncbi.nlm.nih.gov/27588131/

3. Yue, Fangqian, Zou, Yourui, Sun, Shengyu, Huang, Ling, Ma, Hui. . [Knockdown of choline kinase α (CHKA) inhibits the proliferation, invasion and migration of human U87MG glioma cells]. In Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 36, 724-728. doi:. https://pubmed.ncbi.nlm.nih.gov/32958130/

4. Enaw, James O Ebot, Zhu, Huiping, Yang, Wei, Lammer, Edward J, Finnell, Richard H. 2006. CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population. In BMC medicine, 4, 36. doi:. https://pubmed.ncbi.nlm.nih.gov/17184542/

5. Hu, Liang, Wang, Ruo-Yu, Cai, Jian, Zhou, Wei-Ping, Cai, Qing-Ping. . Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma. In Oncotarget, 7, 66660-66678. doi:10.18632/oncotarget.11433. https://pubmed.ncbi.nlm.nih.gov/27556502/

6. Liu, Yanqing, Zhu, Yongping, Gu, Liwei, Dai, Lingyun, Wang, Jigang. 2025. Chloroquine Suppresses Colorectal Cancer Progression via Targeting CHKA and PFKM to inhibit the PI3K/AKT Pathway and the Warburg Effect. In International journal of biological sciences, 21, 1619-1631. doi:10.7150/ijbs.101921. https://pubmed.ncbi.nlm.nih.gov/39990656/

7. Shu, Wan, Hua, Teng, Xin, Xiaoyan, Wang, Hongbo, Zhou, Xing. . Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway. In Carcinogenesis, 46, . doi:10.1093/carcin/bgae059. https://pubmed.ncbi.nlm.nih.gov/39180262/

8. Park, Min-Su, Kim, Su Kang, Shin, Hyun Phil, Lee, Sang Mok, Chung, Joo-Ho. 2012. Association of CHKA polymorphism (rs3794186) with α-fetoprotein levels in hepatocellular carcinoma. In Molecular medicine reports, 6, 1371-4. doi:10.3892/mmr.2012.1081. https://pubmed.ncbi.nlm.nih.gov/22972156/