SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer

Shi, Ming-Yan; Wang, Yarong; Shi, Ying; Tian, Ruo-Fei; Chen, Xiaohong; Zhang, Hai; Wang, Ke; Chen, Zhi‐Nan; Chen, Ruo

doi:10.1016/j.gendis.2023.02.015

Cited by 9 publications

(2 citation statements)

References 42 publications

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“…SETDB1, functioning as a histone lysine methyltransferase, has been reported to mediate lysine methylation of non-histone proteins in various types of cancer, such as non-small cell lung cancer ( 19 , 20 , 27 ). To investigate methylation of cytoplasmic proteins catalyzed by SETDB1, IP and LC-MS analysis were performed to identify methylated residues binding with SETDB1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma

Yang,

Wei,

Wang

et al. 2024

Int J Mol Med

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SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)-dependent pathway, contributing to non-histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelial-mesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNA-seq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcription-quantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of c-MYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain- and loss-of-function approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1-overexpressing MCF7 cells reversed SETDB1-induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, subcellular localization of cytoplasmic SETDB1 may be a pivotal factor in breast cancer progression. The present study offers valuable insight into the novel functions and mechanisms of cytoplasmic SETDB1.

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Section: Resultsmentioning

confidence: 99%

Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma

Yang,

Wei,

Wang

et al. 2024

Int J Mol Med

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“…Then add 100 to each tube μ L cells (1 × 105) and 5 μ L Annexin V-FITC, gently mix at dark conditions and room temperature for 10 min, then add 5 μ L PI, room temperature, dark, incubate for 5 min. Finally, add PBS to 500 μ L. Gently mix and detect within 1 h using a flow cytometry [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

GPX4 is a potential diagnostic and therapeutic biomarker associated with diffuse large B lymphoma cell proliferation and B cell immune infiltration

Chen,

Li,

et al. 2024

Heliyon

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CD147‐K148me2‐Driven Tumor Cell‐Macrophage Crosstalk Provokes NSCLC Immunosuppression via the CCL5/CCR5 Axis

Wang,

Chen,

Lin

et al. 2024

Advanced Science

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Immunosuppression is a major hallmark of tumor progression in non‐small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro‐tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di‐methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di‐methylation of CD147 at Lys148 (CD147‐K148me2) is identified as a common post‐translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147‐K148me2. Further analysis demonstrates that CD147‐K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38‐ZBTB32 signaling, leading to increased NSCLC cell‐derived CCL5 secretion. Subsequently, CD147‐K148me2‐mediated CCL5 upregulation facilitates M2‐like tumor‐associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis‐dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147‐K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147‐K148me2‐driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM‐targeted NSCLC therapy.

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SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer

Cited by 9 publications

References 42 publications

Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma

Cytoplasmic localization of SETDB1‑induced Warburg effect via c‑MYC‑LDHA axis enhances migration and invasion in breast carcinoma

GPX4 is a potential diagnostic and therapeutic biomarker associated with diffuse large B lymphoma cell proliferation and B cell immune infiltration

CD147‐K148me2‐Driven Tumor Cell‐Macrophage Crosstalk Provokes NSCLC Immunosuppression via the CCL5/CCR5 Axis

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