DTX2

Last update 08 May 2025

Basic Info

Synonyms

deltex E3 ubiquitin ligase 2, Deltex2, DTX2

+ [7]

Introduction

Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Functions as a ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity.

100 Clinical Results associated with DTX2

100 Translational Medicine associated with DTX2

0 Patents (Medical) associated with DTX2

Literatures (Medical) associated with DTX2

01 Jul 2025·Drug Resistance Updates

DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma

Article

Author: Mo, Ke ; Niu, Xing ; Huang, Fuxin ; Shen, Cheng ; Zhang, Zhongyan ; Huang, Shanzhou ; Zhang, Chuanzhao ; Zhou, Qi ; Hou, Baohua ; Li, Zhenchong

AIMSEmerging resistance to Lenvatinib, which is used as a first-line agent for the treatment of advanced hepatocellular carcinoma (HCC), is still a concern. The aim of this study was to determine core factors of Lenvatinib resistance (LR) and their underlying molecular mechanisms.METHODSCRISPR screening in HCC cells was conducted, which identified E3 ubiquitin ligase deltex 2 (DTX2) as a core LR-related gene. In vivo and in vitro models were used to clarify the function of DTX2 on LR and ferroptosis. The upstream regulators and downstream effectors of DTX2 were identified, revealing its complex regulatory network.RESULTSDTX2 promoted anti-ferroptosis in LR HCC cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced the ubiquitination-mediated degradation of HSD17B4, resulting in lipid metabolism changes that were associated mainly with docosahexaenoic acid (DHA)-containing PUFAs. Notably, DHA supplements could reverse DTX2-induced anti-ferroptosis and LR. Mechanistically, we uncovered that DTX2 ubiquitinated the HSD17B4 SCP structural domain through its RING structural domain and ubiquitinated the K645 site. The upregulation of DTX2 expression was mediated by JAK2-STAT3 pathway activation. The aberrant activation of STAT3 in acquired LR promoted DTX2 transcription and negatively regulated peroxisomal β-oxidation via K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids levels, leading to the suppression of Lenvatinib-induced ferroptosis in HCC.CONCLUSIONSOur findings suggest that DTX2 attenuates Lenvatinib-induced ferroptosis by inhibiting DHA biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in HCC. The combination of DHA with Lenvatinib could be a promising therapeutic strategy for patients with LR HCC.

01 Feb 2025·Advanced Science

Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor‐associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy

Article

Author: Zhu, Guiqi ; Bu, Yichao ; Wu, Xiaoling ; Zhou, Jian ; Ruan, Yuanyuan ; Zhao, Qianfu ; Fang, Yuan ; Qu, Weifeng ; Chen, Yiran ; Wang, Yi ; Mao, Shengwei ; Liu, Weiren ; Guan, Zhiqi ; Tang, Zheng ; Gao, Jun ; Fan, Jia ; Chen, Fangyu ; Yang, Rui ; Chen, Jiafeng ; Shi, Yinghong ; Chu, Tianhao ; Song, Shushu

AbstractSeveral E3 ligases have been found to affect the immune microenvironment of hepatocellular carcinoma (HCC) and lead to the resistance of immunotherapy. In this study, genes of E3 ligases are screened based on The Cancer Genome Atlas (TCGA) dataset. Through cytometry by time of flight (CyTOF), flow cytometry, and further experiments, Deltex E3 ubiquitin ligase 2 (DTX2) in HCC cells is identified to promote the infiltration and polarization of tumor‐associated neutrophils (TANs) with a protumor phenotype, thus attenuating the infiltration and cytotoxicity of CD8+ T cells partially through C‐X‐C motif chemokine 2 (CXCL2) and C‐X‐C motif chemokine 6 (CXCL6). Mechanistically, DTX2 can interact with histone H2B and promote its monoubiquitination at lysine120 (H2BK120ub1), thereby increasing CXCL2 and CXCL6 transcription through histone epigenetic regulation. Different tumor models in vivo demonstrated that DTX2 inhibitor treatment inhibited tumor growth and sensitized HCC cells to the therapeutic effects of programmed cell death protein 1 (PD‐1) antibody. In summary, this study identifies DTX2 as a potential target for HCC immunotherapy.

17 Dec 2024·Proceedings of the National Academy of Sciences

Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity

Article

Author: Yang, Seungwon ; Kline, Justin ; Zhao, Lijie ; Wilkinson, Emma ; Fan, Hao ; Chen, Jing ; Cui, Yan-Hong ; Peterson, Jack ; Applebaum, Mark A. ; Zou, Zhongyu ; He, Chuan ; Xie, Lishi ; Wei, Jiangbo ; Li, Wenlong ; He, Yu-Ying

Here, we show that vitamin E succinate (VES) acts as a degrader for the m 6 A RNA demethylase fat mass and obesity-associated protein (FTO), thus suppressing tumor growth and resistance to immunotherapy. FTO is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and subsequent degradation in the proteasome. VES binds to FTO and DTX2, leading to enhanced FTO–DTX2 interaction, FTO ubiquitination, and degradation in FTO-dependent tumor cells. VES suppressed tumor growth and enhanced antitumor immunity and response to immunotherapy in vivo in mouse models. Genetic FTO knockdown or VES treatment increased m 6 A methylation in the LIF (Leukemia Inhibitory Factor) gene and decreased LIF mRNA decay, and thus sensitized melanoma cells to T cell–mediated cytotoxicity. Taken together, our findings reveal the underlying molecular mechanism for FTO protein degradation and identify a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance.

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DTX2

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