The PRMT5-LSD1 axis confers Slug dual transcriptional activities and promotes breast cancer progression

Zhang, Jianchao; Fan, Xiaokai; Zhou, Yunfan; Chen, Liang; Rao, Hai

doi:10.1186/s13046-022-02400-7

Cited by 20 publications

(9 citation statements)

References 53 publications

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“…Epithelial to mesenchymal transition (EMT) plays an essential role in metastasis [42]. It has been reported that PRMT5 is involved in Slug-induced EMT in breast cancer [43]. In oral squamous cell carcinoma, PRMT5 enhances metastasis by activating the EMT process [44].…”

Section: Discussionmentioning

confidence: 99%

PRMT5 Promotes Esophageal Carcinoma Metastasis by Enhancing PAK1 Phosphorylation

Zou

Lin

et al. 2023

Preprint

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Background Protein arginine methyltransferase 5 (PRMT5), a member of protein arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a member of serine/threonine protein kinases family, is a cytoskeletal protein playing a critical role in metastasis. This study aimed to explore the potential therapeutic value of PRMT5 and p-PAK1 in esophageal squamous cell carcinoma (ESCC). Methods and results PRMT5 expression in 106 primary human ESCC tissues with their adjacent non-cancerous tissues was detected by immunohistochemistry (IHC). Cell migration was detected by wound healing assays. Finally, we evaluated the clinical significance of PRMT5 combined with PAK1 and p-PAK1 by IHC staining. PRMT5 is upregulated in ESCC and the level of PRMT5 is not only correlated with metastasis but also can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1). IHC assay of human ESCC tissue revealed that the levels of PRMT5 are highly correlated with that of p-PAK1. Kaplan-Meier analysis showed that the OS of patients with PRMT5high/p-PAK1high are significantly shorter than the others (PRMT5high/p-PAK1low, PRMT5low/p-PAK1low, and PRMT5low/p-PAK1high). Conclusions Targeting the PRMT5-p-PAK1 axis is of potential values in ESCC stratification and treatment.

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Section: Discussionmentioning

confidence: 99%

PRMT5 Promotes Esophageal Carcinoma Metastasis by Enhancing PAK1 Phosphorylation

Zou

Lin

et al. 2023

Preprint

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“…PRMT5 regulates arginine symmetrical dimethylation on histone, a critical epigenetic regulator; thus a change in PRMT5 expression has a broad effect on downstream gene expression, in collaboration with another transcriptional regulator [40,41]. Unlike trimethylation on lysine, which usually presents the start of transcription process, the effect of dimethylation is more flexible, including both activation and suppression functions on different histones [42]. Therefore, the aberrant expression of PRMT5 leads to different results for different types of cells and the employment of PRMT5 inhibitors may have a selective effect [43,44].…”

Section: Discussionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

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“…RNA extraction was conducted by using FastPure Cell/Tissue Total RNA Isolation Kit V2 (Vazyme, China) according to the manufacturer's instructions, and residual DNA in the sample is removed by following the instructions and total RNA is obtained. [ 24 ] Reverse transcription was conducted to obtain cDNA, and qPCR was performed with ChamQ Universal SYBR qPCR Master Mix (Vazyme, China). Primers are designed online using primer3.0 (https://primer3.ut.ee/).…”

Section: Methodsmentioning

confidence: 99%

Secretory production of 7‐dehydrocholesterol by engineered Saccharomyces cerevisiae

Ke,

Pan,

et al. 2023

Biotechnology Journal

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Background7‐Dehydrocholesterol (7‐DHC) can be directly converted to vitamin D3 by UV irradiation and de novo synthesis of 7‐DHC in engineered Saccharomyces cerevisiae has been recognized as an attractive substitution to traditional chemical synthesis. Introduction of sterol extracellular transport pathway for the secretory production of 7‐DHC is a promising approach to achieve higher titer and simplify the downstream purification processing.Methods and resultsA series of genes involved in ergosterol pathway were combined reinforced and reengineered in S. cerevisiae. A biphasic fermentation system was introduced and 7‐DHC was found to be enriched in oil‐phase with an increased titer by 1.5‐folds. Quantitative PCR revealed that say1, atf2, pdr5, pry1‐3 involved in sterol storage and transport were all significantly induced in sterol overproduced strain. To enhance the secretion capacity, lipid transporters of pathogen‐related yeast proteins (Pry), Niemann–Pick disease type C2 (NPC2), ATP‐binding cassette (ABC)‐family, and their homologues were screened. Both individual and synergetic overexpression of Plant pathogenesis Related protein‐1 (Pr‐1) and Sterol transport1 (St1) largely increased the de novo biosynthesis and secretory productivity of 7‐DHC, and the final titer reached 28.2 mg g−1 with a secretion ratio of 41.4%, which was 26.5‐folds higher than the original strain. In addition, the cooperation between Pr‐1 and St1 in sterol transport was further confirmed by confocal microscopy, molecular docking, and directed site‐mutation.ConclusionSelective secretion of different sterol intermediates was characterized in sterol over‐produced strain and the extracellular export of 7‐DHC developed in present study significantly improved the cell biosynthetic capacity, which offered a novel modification idea for 7‐DHC de novo biosynthesis by S. cerevisiae cell factory.

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The PRMT5-LSD1 axis confers Slug dual transcriptional activities and promotes breast cancer progression

Cited by 20 publications

References 53 publications

PRMT5 Promotes Esophageal Carcinoma Metastasis by Enhancing PAK1 Phosphorylation

PRMT5 Promotes Esophageal Carcinoma Metastasis by Enhancing PAK1 Phosphorylation

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Secretory production of 7‐dehydrocholesterol by engineered Saccharomyces cerevisiae

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