Latest Publications

@article{mickova_skp2_2021,

title = {Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.},

author = {Alena Mickova and Gvantsa Kharaishvili and Daniela Kurfurstova and Mariam Gachechiladze and Milan Kral and Ondrej Vacek and Barbora Pokryvkova and Martin Mistrik and Karel Soucek and Jan Bouchal},

doi = {10.3390/ijms22062844},

issn = {1422-0067},

year  = {2021},

date = {2021-03-01},

journal = {International journal of molecular sciences},

volume = {22},

number = {6},

abstract = {Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.},

note = {Place: Switzerland},

keywords = {*Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{remsik_tgf-_2020,

title = {TGF-β regulates Sca-1 expression and plasticity of pre-neoplastic mammary epithelial stem cells.},

author = {Ján Remšík and Markéta Pícková and Ondřej Vacek and Radek Fedr and Lucia Binó and Aleš Hampl and Karel Souček},

doi = {10.1038/s41598-020-67827-4},

issn = {2045-2322},

year  = {2020},

date = {2020-07-01},

journal = {Scientific reports},

volume = {10},

number = {1},

pages = {11396},

abstract = {The epithelial-mesenchymal plasticity, in tight association with stemness, contributes to the mammary gland homeostasis, evolution of early neoplastic lesions and cancer dissemination. Focused on cell surfaceome, we used mouse models of pre-neoplastic mammary epithelial and cancer stem cells to reveal the connection between cell surface markers and distinct cell phenotypes. We mechanistically dissected the TGF-β family-driven regulation of Sca-1, one of the most commonly used adult stem cell markers. We further provided evidence that TGF-β disrupts the lineage commitment and promotes the accumulation of tumor-initiating cells in pre-neoplastic cells.},

note = {Place: England},

keywords = {Animal/pathology, Animals, Ataxin-1/*metabolism, Breast Neoplasms/genetics/*pathology, Cell Line, Cell Plasticity/genetics, Epithelial Cells/pathology, Epithelial-Mesenchymal Transition/genetics, ErbB-2/genetics, Experimental/genetics/*pathology, Female, Gene Expression Regulation, Humans, Mammary Glands, Mammary Neoplasms, Mice, Neoplastic, Neoplastic Stem Cells/*pathology, Receptor, Recombinant Proteins/genetics/metabolism, Signal Transduction/genetics, Transforming Growth Factor beta/genetics/*metabolism, Tumor/transplantation},

pubstate = {published},

tppubtype = {article}

}

@article{slabakova_alternative_2017,

title = {Alternative mechanisms of miR-34a regulation in cancer.},

author = {Eva Slabáková and Zoran Culig and Ján Remšík and Karel Souček},

doi = {10.1038/cddis.2017.495},

issn = {2041-4889},

year  = {2017},

date = {2017-10-01},

journal = {Cell death & disease},

volume = {8},

number = {10},

pages = {e3100},

abstract = {MicroRNA miR-34a is recognized as a master regulator of tumor suppression. The strategy of miR-34a replacement has been investigated in clinical trials as the first attempt of miRNA application in cancer treatment. However, emerging outcomes promote the re-evaluation of existing knowledge and urge the need for better understanding the complex biological role of miR-34a. The targets of miR-34a encompass numerous regulators of cancer cell proliferation, survival and resistance to therapy. MiR-34a expression is transcriptionally controlled by p53, a crucial tumor suppressor pathway, often disrupted in cancer. Moreover, miR-34a abundance is fine-tuned by context-dependent feedback loops. The function and effects of exogenously delivered or re-expressed miR-34a on the background of defective p53 therefore remain prominent issues in miR-34a based therapy. In this work, we review p53-independent mechanisms regulating the expression of miR-34a. Aside from molecules directly interacting with MIR34A promoter, processes affecting epigenetic regulation and miRNA maturation are discussed. Multiple mechanisms operate in the context of cancer-associated phenomena, such as aberrant oncogene signaling, EMT or inflammation. Since p53-dependent tumor-suppressive mechanisms are disturbed in a substantial proportion of malignancies, we summarize the effects of miR-34a modulation in cell and animal models in the clinically relevant context of disrupted or insufficient p53 function.},

note = {Place: England},

keywords = {*Genes, Animals, Epigenesis, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Genetic/genetics, Humans, MicroRNAs/*genetics, Neoplasms/*genetics/*pathology, Neoplastic/genetics, Promoter Regions, Tumor Suppressor, Tumor Suppressor Protein p53/*genetics},

pubstate = {published},

tppubtype = {article}

}