Dtx2, encoding Deltex E3 ubiquitin ligase 2, is an E3 ubiquitin ligase that plays diverse roles in multiple biological processes. It is involved in pathways such as Notch signaling, and has significance in cell growth, apoptosis, migration, invasion, and DNA repair [2,4,6,8]. Genetic models, like gene knockout, can be valuable in studying its functions.

In cancer research, Dtx2 has been implicated in promoting the growth of non-small cell lung cancer (NSCLC) cells by inhibiting ferroptosis. Downregulation of Dtx2 suppressed NSCLC cell growth in vitro and in vivo, while its overexpression accelerated cell proliferation. Dtx2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells [1]. In glioma, Dtx2 was highly expressed and silencing it suppressed glioma cell viability, colony formation, and migration, and induced cell apoptosis. Dtx2 could downregulate helicase-like transcription element (HLTF) protein levels by increasing its ubiquitination [2]. In hepatocellular carcinoma, Dtx2 promoted anti-ferroptosis in Lenvatinib-resistant cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4, which led to lipid metabolism changes [3]. In colorectal cancer, Dtx2 overexpression promoted cell migration and invasion through the Notch2/Akt axis [4]. In telomerase-positive cancer cells, Dtx2 depletion downregulated human telomerase reverse transcriptase (hTERT) transcription and telomerase activity, contributing to growth arrest and increased apoptosis [7]. In RUNX1-dependent leukemia cells, Dtx2 overexpression showed a growth-inhibitory effect as it bound to RUNX1, inhibited its acetylation and reduced its transcriptional activity [5].

In conclusion, Dtx2 is an important E3 ubiquitin ligase with a significant impact on cancer development and progression, as demonstrated through various loss-of-function studies. Its role in regulating ferroptosis, cell growth, and migration in different cancer types highlights its potential as a therapeutic target. Additionally, in zebrafish, Dtx2 deficiency induced ependymo-radial glial cell proliferation and improved spinal cord motor function recovery, suggesting its role in neural regeneration [6].

References:

1. Liu, Zhuang, Liu, Chang, Fan, Caihong, Qi, Zhi, Shen, Yanna. 2024. E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 77, 101154. doi:10.1016/j.drup.2024.101154. https://pubmed.ncbi.nlm.nih.gov/39366066/

2. Li, Ren, Chen, Yang, Yang, Biao, Zhao, Yuanli, Guo, Geng. 2024. DTX2 promotes glioma development via regulation of HLTF. In Biology direct, 19, 2. doi:10.1186/s13062-023-00447-w. https://pubmed.ncbi.nlm.nih.gov/38163902/

3. Zhang, Zhongyan, Zhou, Qi, Li, Zhenchong, Zhang, Chuanzhao, Huang, Shanzhou. 2025. DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 81, 101224. doi:10.1016/j.drup.2025.101224. https://pubmed.ncbi.nlm.nih.gov/40058099/

4. Ma, Z, Zhao, X, Zhang, X, Xu, G, Liu, F. . [DTX2 overexpression promotes migration and invasion of colorectal cancer cells through the Notch2/Akt axis]. In Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 43, 340-348. doi:10.12122/j.issn.1673-4254.2023.03.02. https://pubmed.ncbi.nlm.nih.gov/37087577/

5. Yonezawa, Taishi, Takahashi, Hirotaka, Hao, Yangying, Kitamura, Toshio, Goyama, Susumu. 2023. The E3 ligase DTX2 inhibits RUNX1 function by binding its C terminus and prevents the growth of RUNX1-dependent leukemia cells. In The FEBS journal, 290, 5141-5157. doi:10.1111/febs.16914. https://pubmed.ncbi.nlm.nih.gov/37500075/

6. Chen, Hao-Yuan, Huang, Yin-Cheng, Yeh, Tu-Hsueh, Sun, Mu-Qun, Cheng, Yi-Chuan. 2024. Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery. In Stem cells and development, 33, 540-550. doi:10.1089/scd.2023.0247. https://pubmed.ncbi.nlm.nih.gov/39001828/

7. Zhou, Zhifen, Li, Yujing, Xu, Huimin, Ma, Wenbin, Songyang, Zhou. 2022. An inducible CRISPR/Cas9 screen identifies DTX2 as a transcriptional regulator of human telomerase. In iScience, 25, 103813. doi:10.1016/j.isci.2022.103813. https://pubmed.ncbi.nlm.nih.gov/35198878/

8. Djerir, Billel, Marois, Isabelle, Dubois, Jean-Christophe, Orthwein, Alexandre, Maréchal, Alexandre. 2024. An E3 ubiquitin ligase localization screen uncovers DTX2 as a novel ADP-ribosylation-dependent regulator of DNA double-strand break repair. In The Journal of biological chemistry, 300, 107545. doi:10.1016/j.jbc.2024.107545. https://pubmed.ncbi.nlm.nih.gov/38992439/