ABSTRACTAdult T‐cell leukemia (ATL) is an aggressive malignancy caused by human T‐cell leukemia virus type 1 (HTLV‐1) infection. Enhancer of zeste homolog 2 (EZH2) has been implicated in the development and progression of multiple cancers, including virus‐induced malignancies. However, the potential function of EZH2 in HTLV‐1‐induced oncogenesis has not been clearly elucidated. In the present study, we showed that EZH2 was overexpressed and activated in HTLV‐1‐infected cell lines, potentially due to the activation of EZH2 promoter by HTLV‐1 Tax and NF‐κB p65 subunit. In addition, we found that EZH2 enhanced the HBZ‐induced activation of TGF‐β signaling in a histone methyltransferase‐independent manner. As a mechanism for these actions, we found that EZH2 targeted Smad3/Smad4 to form a ternary complex, and the association between Smad3 and Smad4 was markedly enhanced in the presence of EZH2. Knockdown of EZH2 in ATL cells indeed repressed the expressions of the TGF‐β target genes. In particular, EZH2 synergistically enhanced the HBZ/TGF‐β‐induced Foxp3 expression. Treatment of 3‐Deazaneplanocin A, a specific inhibitor of EZH2 significantly inhibited the Foxp3 expression. Taken together, our results suggest that EZH2 may be involved in the differentiation of regulatory T cells through activating the HBZ‐Smad3‐TGF‐β signaling axis, which is considered to be a key strategy for viral persistence.

2024-10-24·Journal of Medicinal Chemistry

3-Deazaneplanocin A (DZNep): A Drug That Deserves a Second Look

Review

作者: Marquez, Victor E.

The emerging data compiled during the past five years on 3-deazaneplanocin (DZNep) provide compelling evidence to reevaluate this drug as a better alternative over the specific catalytic inhibitors of histone methyl transferases (HTMs). The indirect mechanism of DZNep via inhibition of AdoHcy-ase, once considered a liability due to possible side effects, has now shown to be rather beneficial as additional pathways targeted by DZNep are important contributors to its superior anticancer properties. Furthermore, DZNep has demonstrated the ability to induce proteasomal degradation of its target and reduce toxicity in combination with well-established antitumor therapies in animal models. In addition, DZNep has shown important effects in suppressing fibrosis and inflammation in liver, kidney, peritoneum, and airways. Finally, inhibition of mRNA m⁶A methylation by DZNep suppresses the synthesis of the viral genome in SARS-Cov-2 infection and promises to have important therapeutic value when combined with its potent antiviral efficacy and anti-inflammatory effects.

2024-06-01·International Journal of Biological Macromolecules

Structural basis for substrate recognition by a S-adenosylhomocysteine hydrolase Lpg2021 from Legionella pneumophila

Article

作者: Xie, Rao ; Wang, Weiqiang ; Wang, Xu ; Ge, Honghua ; Chen, Yanan ; Gao, Yongshan ; Wang, Min ; Ma, Jinming ; Wang, Na ; Yang, Beibei ; Hua, Lan

S-Adenosyl-l-homocysteine hydrolase (SAHH) is a crucial enzyme that governs S-adenosyl methionine (SAM)-dependent methylation reactions within cells and regulates the intracellular concentration of SAH. Legionella pneumophila, the causative pathogen of Legionnaires' disease, encodes Lpg2021, which is the first identified dimeric SAHH in bacteria and is a promising target for drug development. Here, we report the structure of Lpg2021 in its ligand-free state and in complexes with adenine (ADE), adenosine (ADO), and 3-Deazaneplanocin A (DZNep). X-ray crystallography, isothermal titration calorimetry (ITC), and molecular docking were used to elucidate the binding mechanisms of Lpg2021 to its substrates and inhibitors. Virtual screening was performed to identify potential Lpg2021 inhibitors. This study contributes a novel perspective to the understanding of SAHH evolution and establishes a structural framework for designing specific inhibitors targeting pathogenic Legionella pneumophila SAHH.

100 项与 3-deazaneplanocin A 相关的药物交易

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