ELK4, also known as ETS domain-containing protein Elk-4, is a member of the ternary complex factor (TCF) subfamily of Ets transcription factors and a downstream effector of MAPK signaling, critical for cell proliferation [5]. It is involved in various biological processes and disease-related pathways.

In cancer research, ELK4 has been found to promote the progression of multiple cancers. In colorectal cancer, it promotes tumorigenesis by activating the neoangiogenic factor LRG1 in a non-canonical SP1/3-dependent manner, and its phosphorylation by IGF1R-phosphorylated PYCR1 facilitates its transcriptional activity and sustains tumor growth under hypoxia [1,2]. In NSCLC, a tRNA-derived fragment AS-tDR-007333 promotes malignancy by stimulating ELK4 expression, which then binds to the MED29 promoter and increases its transcription [3]. In HPV-associated cervical cancer, ELK4 promotes cell cycle progression and stem cell-like characteristics by regulating the FBXO22/PTEN axis [6]. In gastric cancer, it promotes the development by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis [9]. In skin cutaneous melanoma, ELK4 enhances proliferation, invasion, migration and inhibits ferroptosis by upregulating CHMP6 transcription [8]. In mast cells, Elk4 knockout suppresses cell proliferation, impedes the cell cycle, diminishes cytokine/chemokine transcriptional activation, and enhances degranulation [5]. In the context of obstructive sleep apnea, overexpression of ELK4 in mice attenuates neuroinflammation and cognitive dysfunction by inducing the transcription of FNDC5 [4]. Also, hydrogen sulfide in colorectal cancer inhibits CD8+ T-cell migration by increasing AAK-1 expression via ELK4 persulfidation [7].

In conclusion, ELK4 is a transcription factor with a significant impact on cell proliferation, immune-related responses, and inflammation in various disease conditions, especially cancers. Gene knockout models in mast cells and in vivo studies in mice with obstructive sleep apnea have been crucial in revealing these functions, providing potential therapeutic targets for related diseases.

References:

1. Zheng, Ke, Sha, Nannan, Hou, Guofang, Jiang, Yuhui, Chen, Tao. 2023. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. In Nature communications, 14, 6117. doi:10.1038/s41467-023-41658-z. https://pubmed.ncbi.nlm.nih.gov/37777542/

2. Zhu, Zhehui, Guo, Yuegui, Liu, Yun, Goel, Ajay, Liu, Chen-Ying. 2023. ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2303378. doi:10.1002/advs.202303378. https://pubmed.ncbi.nlm.nih.gov/37786278/

3. Yang, Wenhan, Gao, Kaiping, Qian, Youhui, Zheng, Duo, Zhai, Rihong. 2022. A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes. In Journal of hematology & oncology, 15, 53. doi:10.1186/s13045-022-01270-y. https://pubmed.ncbi.nlm.nih.gov/35526007/

4. Yang, Haiming, Yuan, Ying, Yang, Ke, Wang, Ning, Li, Xiao. 2024. ELK4 ameliorates cognitive impairment and neuroinflammation induced by obstructive sleep apnea. In Brain research bulletin, 216, 111054. doi:10.1016/j.brainresbull.2024.111054. https://pubmed.ncbi.nlm.nih.gov/39173777/

5. Huang, Yuji, Zhu, Zhehui, Li, Weize, Liu, Chen-Ying, Li, Li. 2023. ELK4 exerts opposite roles in cytokine/chemokine production and degranulation in activated mast cells. In Frontiers in immunology, 14, 1171380. doi:10.3389/fimmu.2023.1171380. https://pubmed.ncbi.nlm.nih.gov/37529050/

6. Gao, Fuxian, Wang, Chunxiao, Bai, Xue, Ji, Jianghai, Huang, Xinrui. 2023. ELK4 Promotes Cell Cycle Progression and Stem Cell-like Characteristics in HPV-associated Cervical Cancer by Regulating the FBXO22/PTEN Axis. In Balkan medical journal, 40, 409-414. doi:10.4274/balkanmedj.galenos.2023.2023-4-66. https://pubmed.ncbi.nlm.nih.gov/37519006/

7. Yue, Taohua, Li, Jichang, Zhu, Jing, Wang, Pengyuan, Chen, Shanwen. . Hydrogen Sulfide Creates a Favorable Immune Microenvironment for Colon Cancer. In Cancer research, 83, 595-612. doi:10.1158/0008-5472.CAN-22-1837. https://pubmed.ncbi.nlm.nih.gov/36525473/

8. Li, Haiyan, Chen, Zedong, Huang, Yuanjie, Chen, Chen, Cai, Limin. 2024. ELK4 targets CHMP6 to inhibit ferroptosis and enhance malignant properties of skin cutaneous melanoma cells. In Archives of dermatological research, 316, 634. doi:10.1007/s00403-024-03367-5. https://pubmed.ncbi.nlm.nih.gov/39305302/

9. Zheng, Lei, Xu, Hongmei, Di, Ya, Kang, Liying, Gao, Liming. 2021. ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis. In Journal of translational medicine, 19, 342. doi:10.1186/s12967-021-02915-1. https://pubmed.ncbi.nlm.nih.gov/34372882/