Uveal Melanoma zebrafish xenograft models illustrate the mutation status-dependent effect of compound synergism or antagonism DOI Creative Commons

Quincy van den Bosch,

Emine Kılıç, Erwin Brosens

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: April 24, 2024

Abstract Purpose Uveal melanoma (UM) is the most common primary intraocular malignancy with a high probability of metastatic disease. Although excellent treatment option for UM are available, therapy disease remain limited. Drug discovery studies using mouse models have thus far failed to provide therapeutic solutions, highlighting need novel models. Here, we optimize zebrafish xenografts as potential model drug by showcasing behavior multiple cell lines and findings on mutation-dependent compound synergism/antagonism Z-Tada; an algorithm objectively characterize output measurements. Methods Prognostic relevant or healthy melanocytes were inoculated at three distinct inoculation sites. Standardized quantifications independent site obtained measure tumor burden number, size distance disseminated cells. Sequentially, utilized this validate combinatorial synergism antagonism seen in vitro. Results Detailed analysis 691 demonstrated perivitelline space provided robust data dissemination. Cell more invasive (SF3B1mut BAP1mut) behaved aggressive in model. Combinatorial illustrated mutation-dependent, which confirmed vivo. differed per xenograft-model, it either inhibited overall Conclusion Perivitelline provides ability high-throughput screening acquisition Z-Tada. This demonstrates that uveal must take mutational subclasses into account, especially discoveries.

Language: Английский

MITF in Normal Melanocytes, Cutaneous and Uveal Melanoma: A Delicate Balance DOI Open Access
Maria C. Gelmi, Laurien E. Houtzagers, Thomas Strub

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6001 - 6001

Published: May 26, 2022

Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role MITF uveal melanoma (UM) not explored much detail. We review literature about normal melanocytes, UM. In regulates development, melanin synthesis, survival. The expression profile behaviour MITF-expressing cells suggest that promotes local proliferation inhibits invasion, inflammation, epithelial-to-mesenchymal (EMT) transition. Loss leads to increased invasion inflammation more prevalent malignant cells. Cutaneous switch between MITF-high MITF-low states different phases tumour UM, loss associated with BAP1 protein expression, which a marker poor prognosis. These data indicate dual for benign melanocytic

Language: Английский

Citations

55
Anticancer properties of histone deacetylase inhibitors – what is their potential? DOI
Kajetan Kiełbowski, Agata Szwedkowicz,

Paulina Plewa

et al.

Expert Review of Anticancer Therapy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Jan. 10, 2025

Introduction Histone modifications are crucial epigenetic mechanisms for regulating gene expression. acetyltransferases and deacetylases (HDACs) catalyze histone acetylation, a process that mediates transcription. Over recent decades, studies have demonstrated targeting acetylation can be effective in cancer treatment, leading to the development approval of several HDAC inhibitors.

Language: Английский

Citations

1
Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma DOI Creative Commons
Ai Zhuang, Xiang Gu,

Tongxin Ge

et al.

Cancer Communications, Journal Year: 2023, Volume and Issue: 43(11), P. 1185 - 1206

Published: July 19, 2023

Abstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m 6 A) is the most prevalent messenger RNA modification that plays an essential role regulation of tumorigenesis. Howbeit, in‐depth understanding crosstalk between acetylation and m A modifications remains enigmatic. This study aimed to explore tumorigenesis ocular melanoma. Methods Histone inhibitor screening was used effects HDACis on melanoma cells. Dot blot assay detect global level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets tagmentation, single‐cell sequencing, methylated immunoprecipitation‐sequencing (meRIP‐seq), individual nucleotide resolution cross‐linking (miCLIP‐seq), were performed reveal mechanisms methyltransferase‐like 14 ( METTL14 ) FAT tumor suppressor homolog 4 FAT4 Quantitative real‐time polymerase chain reaction (qPCR), western blotting, immunofluorescent staining applied expression cells tissues. Cell models orthotopic xenograft established determine roles growth RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, stability adopted investigate mechanism by which levels affected. Results First, we found presented vulnerability towards HDACis. triggered elevation Further studies revealed served as a downstream candidate for silenced hypo‐histone status, whereas HDACi restored normal level , thereby inducing its expression. Subsequently, promoting suppressor, A‐YTH N6‐methyladenosine 1‐dependent manner. Taken together, subsequently elicited METTL14‐mediated Conclusions These results demonstrate exert anti‐cancer orchestrating modification, unveiling “histone‐RNA crosstalk” HDAC/ / epigenetic cascade

Language: Английский

Citations

12
Characterization of a Water Soluble Quininib Prodrug that Blocks Metabolic Activity and Proliferation of Multiple Cancer Cell Lines DOI Creative Commons
Valentina Tonelotto,

Alina Qaisar,

Eavan C. McLoughlin

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117727 - 117727

Published: May 1, 2025

Language: Английский

Citations

0
Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases DOI Creative Commons
Jianglei Li,

Meihong Yu,

Fu S

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: May 16, 2022

The deacetylation process regulated by histone deacetylases (HDACs) plays an important role in human health and diseases. HDAC6 belongs to the Class IIb of HDACs family, which mainly modifies non-histone proteins located cytoplasm. a key tumors, neurological diseases, inflammatory Therefore, targeting has become promising treatment strategy recent years. ACY-1215 is first orally available highly selective inhibitor, its efficacy therapeutic effects are being continuously verified. This review summarizes research progress cancer other as well underlying mechanism, order guide future clinical trials more in-depth mechanism researches.

Language: Английский

Citations

16
MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway DOI Creative Commons
Yanru Guo,

Laia Ollé,

Elizabeth Proaño-Pérez

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 10, 2023

MRGPRX2, a G-protein-coupled-seven transmembrane domain receptor, is mainly expressed in mast cells and neurons involved skin immunity pain. It implicated the pathophysiology of non-IgE-mediated immediate hypersensitivity has been related to adverse drug reactions. Moreover, role proposed asthma, atopic dermatitis, contact chronic spontaneous urticaria. Although it prominent disease, its signaling transduction poorly understood. This study shows that MRGPRX2 activation with substance P increased Lysyl t-RNA synthetase (LysRS) translocation nucleus. LysRS moonlighting protein dual translation IgE cells. Upon allergen- IgE-FcεRI crosslinking, translocated nucleus activates microphthalmia-associated transcription factor (MITF) activity. In this study, we found triggering led MITF phosphorylation Therefore, overexpression activity after activation. silencing reduced MRGPRX2-dependent calcium influx cell degranulation. Furthermore, pathway inhibitor, ML329, impaired expression, influx, drugs such as atracurium, vancomycin, morphine, reported induce degranulation, Altogether, our data show enhances activity, abrogation by or inhibition resulted defective We conclude involves pathway. Thus, MITF-dependent targets may be considered therapeutic approaches treat pathologies where implicated.

Language: Английский

Citations

9
MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation DOI Open Access
Elizabeth Proaño-Pérez,

Laia Ollé,

Yanru Guo

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3515 - 3515

Published: Feb. 9, 2023

Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance highlight the need for alternative treatment strategies. Previously, we reported that adaptor molecule SH3 binding protein 2 (SH3BP2 3BP2) regulates expression at transcriptional level microphthalmia-associated transcription factor (MITF) post-transcriptional human mast cells tumor (GIST) cell lines. Lately, found SH3BP2 pathway MITF through miR-1246 miR-5100 GIST. In this study, were validated by qPCR SH3BP2-silenced leukemia line (HMC-1). MiRNA overexpression reduces MITF-dependent target HMC-1. The same pattern was observed after silencing. addition, inhibitor ML329 affects viability cycle progression We also examine whether downregulation affected IgE-dependent degranulation. overexpression, silencing, reduced degranulation LAD2- CD34+-derived cells. These findings suggest may be a potential therapeutic allergic reactions deregulated mast-cell-mediated disorders.

Language: Английский

Citations

8
Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line DOI Open Access
Nami Nishikiori, Megumi Watanabe, Tatsuya Sato

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(2), P. 263 - 263

Published: Jan. 7, 2024

To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) presence or absence of low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM lines including SK-mel-24, A375, dabrafenib- trametinib-resistant A375 (A375DT), WM266-4. Upon exposure to 2 10 μM viability was significantly decreased WM266-4, A375DT cells, but not a dose-dependent manner, these toxic ML329 most evident WM266-4 cells. Extracellular flux assays conducted using Seahorse bioanalyzer revealed that treatment with increased basal respiration, ATP-linked proton leakage, non-mitochondrial respiration cells glycolytic function SK-mel-24 whereas there no marked A stress assay under conditions high glucose concentrations also demonstrated effect dose-dependent. In addition, 3D-spheroid-forming ability, though variable lines. Furthermore, mRNA expression levels selected genes, STAT3 as possible regulator 3D formation, KRAS SOX2 oncogenic-signaling-related factors, PCG1a main mitochondrial biogenesis, HIF1a major hypoxia transcriptional regulator, fluctuated lines, possibly supporting diverse mentioned above. The findings various suggest MITF-associated activities are different types MM.

Language: Английский

Citations

2
Identification of targetable epigenetic vulnerabilities in uveal melanoma DOI Creative Commons
Gulum Yenisehirli,

Sebastian Borges,

Steffanie S. Braun

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, which preferentially metastasizes to liver approximately half of all cases. Metastatic UM notoriously resistant therapy and almost uniformly fatal. metastasis strongly associated with mutational inactivation

Language: Английский

Citations

2
1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model DOI Creative Commons
Kayleigh Slater,

Rosa Bosch,

Kaelin Francis Smith

et al.

Frontiers in Medicine, Journal Year: 2023, Volume and Issue: 9

Published: Jan. 9, 2023

Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) metastatic UM (MUM) 1.07 years, a reported range of 0.84-1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT1) expression associates poor outcomes. CysLT1 antagonists, quininib and 1,4-dihydroxy quininib, alter hallmarks cell lines in vitro. Here, the clinical relevance CysLT receptors therapeutic potential analogs elaborated using preclinical vivo orthotopic xenograft models ex patient samples. Immunohistochemical staining independent cohort (n = 64) patients confirmed significantly death from disease (p 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying UM. samples 11) cultured as explants, alters secretion IL-13, IL-2, TNF-α. orthotopic, line-derived model MUM, administered intraperitoneally at 25 mg/kg decreases ATP5B 0.03), marker oxidative phosphorylation. ATP5F1B prognostic indicator, whereas low ATP5F1B, combination disomy 3, correlates absence TCGA-UM dataset. These data highlight diagnostic companion to treat MUM.

Language: Английский

Citations

5