THEM4, also known as carboxyl‑terminal modulator protein 1 (CTMP1), is a member of the thioesterase superfamily. It has acyl-CoA thioesterase activity and is involved in lipid metabolism [4,7]. It is also an Akt kinase-binding protein, playing a significant role in the Akt pathway, which regulates growth, proliferation, and metabolism of tumor cells and stem cells, thus impacting the development and treatment of various diseases [1].

Some studies suggest that THEM4 initially was considered an endogenous inhibitor of Akt, inhibiting Akt phosphorylation in diseases like lung, pancreatic, and liver cancers [1]. However, it was later found to promote tumor cell proliferation by positively regulating Akt activity in breast and nasopharyngeal carcinomas [1]. In cholangiocarcinoma, CARD9 promotes cancer progression by interacting with THEM4, facilitating AKT and mTOR phosphorylation [2]. Exosomal miR-183-5p in colon cancer targets THEM4 to activate the PI3K/AKT and NF-κB pathways, promoting cancer development [3]. In glioma, ENOPH1 activates the PI3K/AKT/mTOR signaling pathway by regulating THEM4, promoting cell proliferation and migration [5]. Vitamin D suppresses the Akt/NF-κB/COX-2 pathway through up-regulation of THEM4, restraining macrophage-mediated inflammatory processes [6].

In conclusion, THEM4 is a key player in multiple biological processes mainly through its association with the Akt pathway. Its dual role in regulating Akt phosphorylation in different cancers reveals its complexity in disease mechanisms. Functional studies of THEM4 in disease conditions, especially in cancer, contribute to a better understanding of disease pathogenesis and may offer potential therapeutic targets.

References:

1. Xie, Wen, Liu, Weidong, Wang, Lei, Liu, Jie, Ren, Caiping. . Roles of THEM4 in the Akt pathway: a double-edged sword. In Journal of Zhejiang University. Science. B, 25, 541-556. doi:10.1631/jzus.B2300457. https://pubmed.ncbi.nlm.nih.gov/39011675/

2. Zhang, Tao, Zhu, Li-Xin, Sun, Qi-Kai, Chen, Li-Jian, Qian, Ye-Ben. 2024. CARD9 promotes cholangiocarcinoma by regulating the IL-17A/Hedgehog and the THEM4/AKT/mTOR signaling pathways. In International immunopharmacology, 143, 113399. doi:10.1016/j.intimp.2024.113399. https://pubmed.ncbi.nlm.nih.gov/39418733/

3. Zhang, Shangxin, Li, Deguan, Zhao, Min, Wang, Zhenjun, Li, Yongxiang. 2021. Exosomal miR-183-5p Shuttled by M2 Polarized Tumor-Associated Macrophage Promotes the Development of Colon Cancer via Targeting THEM4 Mediated PI3K/AKT and NF-κB Pathways. In Frontiers in oncology, 11, 672684. doi:10.3389/fonc.2021.672684. https://pubmed.ncbi.nlm.nih.gov/34249713/

4. Brocker, Chad, Carpenter, Christopher, Nebert, Daniel W, Vasiliou, Vasilis. . Evolutionary divergence and functions of the human acyl-CoA thioesterase gene ( ACOT ) family. In Human genomics, 4, 411-20. doi:. https://pubmed.ncbi.nlm.nih.gov/20846931/

5. Wang, Bo, Xu, Xin, Liu, Xi, Han, Tong, Hong, Jian. 2020. Enolase-phosphatase 1 acts as an oncogenic driver in glioma. In Journal of cellular physiology, 236, 1184-1194. doi:10.1002/jcp.29926. https://pubmed.ncbi.nlm.nih.gov/32654229/

6. Wang, Qingsong, He, Yuhu, Shen, Yujun, Wang, Junwen, Yu, Ying. 2014. Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4. In The Journal of biological chemistry, 289, 11681-11694. doi:10.1074/jbc.M113.517581. https://pubmed.ncbi.nlm.nih.gov/24619416/

7. Nguyen, Huonggiang, Kim, Seon-Hwan, Juang, Uijin, Kwon, So Hee, Park, Jongsun. 2024. Overview of carboxyl‑terminal modulator protein 1 and its importance in various metabolic regulations (Review). In Molecular medicine reports, 30, . doi:10.3892/mmr.2024.13282. https://pubmed.ncbi.nlm.nih.gov/38994770/