Cell Chemical Biology
·
2024
·
IF 6.6
KeJing Zhang,Juan Wei,SheYu Zhang,Liyan Fei,Lu Guo,Xueying Liu,YiShuai Ji,WenJun Chen,Felipe E. Ciamponi,WeiChang Chen,MengXi Li,Jie Zhai,Ting Fu,Katlin B. Massirer,Yang Yu,Mathieu Lupien,Yong Wei,Cheryl. H. Arrowsmith,Qin Wu,WeiHong Tan
Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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药理学
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DOI
PubMed
高影响因子
Molecular Cancer
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2022
·Vol. 21
·期 1
·1-23
·
IF 41.444
Yao Bing,Zhu Sha,Wei Xiyi,Chen Ming-Kun,Feng Yangkun,Li Zhimin,Xu Xinyu,Zhang Yuwei,Wang Yang,Zhou Jingwan,Tang Ningyuan,Ji Chengjian,Jiang Peng,Zhao Shan-Chao,Qin Chao,Feng Ninghan
Background Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies.Methods A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues.Results Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5.Conclusion sOur findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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癌症生物学
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分子遗传学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-15
·
IF 9.3
Zheng Yingxia,Chen Zheyi,Zhou Bingqian,Chen Shiyu,Chen Ningdai,Shen Lisong
Background Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated.Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms.Results We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice.Conclusion sOur study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases.
研究领域:
免疫学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2026
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IF 3.2
Rongli Sun,Kai Xu,Xiaoqin Li,Jiawei Huang,Daqin Wang,Yuepu Pu,Juan Zhang
Benzene causes SIRT6 inhibition which enhances glycolysis and lactate accumulation. • The increased lactate thus drives DSBs and cellular senescence in benzene toxicity. • SIRT6 regulates PRMT5 lactylation at lysine 240 (K240) via enzymes TIP60 and HDAC1. • Blocking PRMT5 K240 lactylation mitigates BQ-caused DNA damage and senescence. Benzene exposure induces hematotoxicity, partially through disrupted DNA damage repair. SIRT6 is a key regulator of both DNA repair and metabolism. While its connection to metabolic reprogramming and novel lactylation modifications in benzene toxicity remains unknown. Herein, we found decreased SIRT6 expression in the peripheral WBCs of benzene-exposed workers. Furthermore, mediation analysis identified SIRT6, p16, and serum γ-H2AX levels as mediators of the inverse relationship between urinary S-PMA and WBC counts. In vitro , benzoquinone (BQ) suppressed SIRT6, enhanced glycolysis and lactate production, and induced DNA double-strand breaks (DSBs) and senescence. SIRT6-knockdown models confirmed that SIRT6 deficiency exacerbates benzene-induced increase in glycolysis and lactate accumulation. Crucially, lactate reduction with DCA attenuated DSBs and cellular senescence in bone marrow cells, mitigating hematopoietic damage. Mechanistically, we identified PRMT5 as a novel lactylation target of SIRT6 at lysine 240 (K240), a process that SIRT6 regulated through the lactyltransferase TIP60 and delactylase HDAC1. Functional studies in K240-mutant cells demonstrated that blocking lactylation at this site alleviated BQ-induced DSBs and senescence. Our findings establish that SIRT6 deficiency drives a lactate-fuelled lactylation of PRMT5 at K240, impairing DNA repair and promoting hematopoietic stem cell senescence caused by benzene. This work elucidates a previously unrecognized metabolic-epigenetic axis in benzene toxicity and highlights the therapeutic potential of targeting glycolytic flux or specific lactylation events to combat chemical-induced hematological damage. Download: Download high-res image (245KB) Download: Download full-size image
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DOI
高影响因子
HISTOLOGY AND HISTOPATHOLOGY
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2025
·
IF 2
Zhanqiang Zhai,Chunwei Xu,Yonghua Min,Youcai Zhu,Xiaofeng Li
Objectives: The potential treatment option of targeting protein arginine methyltransferase 5 (PRMT5) has been explored, but further investigation is required to assess the efficacy of combination therapy in non-small cell lung cancer (NSCLC). In this study, bioinformatics and online databases were utilized to select the combined therapeutic targets. Methods: The potential kinases associated with PRMT5-related genes in NSCLC were analyzed using The Cancer Genome Atlas (TCGA) database and X2K Appyter (Expression2Kinases) database. In vitro evaluations were conducted to assess the synergistic effects between PRMT5 and cyclin-dependent kinase 1 (CDK1) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cell lines. Results: In our study, CDK1 was primarily the kinase associated with PRMT5-related genes in NSCLC. We observed a significant upregulation of PRMT5 and CDK1 expression in NSCLC tissues. Methylthioadenosine phosphorylase (MTAP)-null NSCLC cell lines demonstrated sensitivity to monotherapy with PRMT5i. A considerable synergistic effect was observed in MTAP-null cells when combining PRMT5i with CDK1i, resulting in the inhibition of cell growth and migration. Conclusion: Our research provides evidence supporting the synergistic anti-tumor effects of targeting PRMT5 and CDK1 in MTAP-deficient NSCLC.
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2022
·
IF 6.064
Haoran Mu,Chenlu Liu,Qi Zhang,Huanliang Meng,Shimin Yu,Ke Zeng,Jing Han,Xinmeng Jin,Shi Shi,Peiyao Yu,Tianlong Li,Jing Xu,Yingqi Hua
Background: Drugs based on synthetic lethality have advantages such as inhibiting tumor growth and affecting normal tissue in vivo . However, specific targets for osteosarcoma have not been acknowledged yet. In this study, a non-targeted but controllable drug delivery system has been applied to selectively enhance synthetic lethality in osteosarcoma in vitro , using the magnetic-driven hydrogel microrobots. Methods: In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug. Then, the drug was carried by hydrogel microrobots containing Fe 3 O 4 . Morphological characteristics of the microrobots were detected using electron microscopy. In vitro drug effect was detected by the CCK-8 assay kit, Western blotting, etc. Swimming of microrobots was observed by a timing microscope. Selective inhibition was verified by cultured tumors in an increasing magnetic field. Results: Genomic mutation of MTAP deletion occurred commonly in pan-cancer in the TCGA database (nearly 10.00%) and in osteosarcoma in the TARGET database (23.86%). HOS and its derivatives, 143B and HOS/MNNG, were detected by MTAP deletion according to the CCLE database and RT-PCR. EPZ015666, the PRMT5 inhibitor, could reduce the SDMA modification and inhibition of tumor growth of 143B and HOS/MNNG. The hydrogel microrobot drug delivery system was synthesized, and the drug was stained by rhodamine. The microrobots were powered actively by a magnetic field. A simulation of the selected inhibition of microrobots was performed and lower cell viability of tumor cells was detected by adding a high dose of microrobots. Conclusion: Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field.
研究领域:
生物医学工程
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肿瘤学
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药理学
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材料科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2025
·Vol. 15
·期 29
·23966
·
IF 4.6
Yi Liu,Zheng Zhang,Huyang Du,Xiangjun Chen,Nan Hu,Tingting Yu,Meili Hou,Xiaolin Yu
Chemoresistance poses a critical challenge in cancer therapy across diverse tumor types, including non-small cell lung cancer (NSCLC), where chemotherapy-induced neuroendocrine differentiation (NED) of tumor cells plays a pivotal role in acquiring treatment resistance. This process significantly reduces chemotherapy efficacy, accelerates tumor progression, and ultimately worsens patient survival outcomes. The complex mechanisms underlying chemoresistance involve multiple factors, including enhanced DNA repair pathways, increased drug efflux capacity, and alterations in gene expression. Additionally, the tumor microenvironment, a dynamic ecosystem surrounding cancer cells, fosters a protective niche that exacerbates chemotherapy resistance. To address this challenge, we propose an innovative nanocomposite hydrogel system for the co-delivery of cisplatin and short hairpin RNA (shRNA) targeting protein arginine methyltransferase 5 (PRMT5), a key gene implicated in drug resistance. This system utilizes polyethyleneimine-modified mesoporous silica nanoparticles, which serve as nanocarriers, encapsulating cisplatin within the mesopores and coating the surface with methacryloylated hyaluronic acid (HA-MA). The design enables tumor microenvironment-responsive drug release, triggered by hyaluronidase enzymes abundant within the tumor, resulting in nanoparticle disassembly and the release of cisplatin. Simultaneously, the delivery of shRNA silences PRMT5 expression, enhancing chemosensitivity. By integrating targeted gene therapy with chemotherapy, this system offers a promising strategy for overcoming chemoresistance in NSCLC. Targeting both cancer cells and their microenvironment, this approach holds potential to transform the treatment of chemotherapy-resistant cancers, advancing more effective and personalized oncological therapies. An enzyme-responsive hydrogel to co-deliver cisplatin and shRNA, targeting NED-driven chemoresistance in NSCLC.
研究领域:
肿瘤学
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纳米医学
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药物递送
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分子生物学
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癌症治疗
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生物材料
✓ 已验证
DOI
PubMed
高影响因子
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