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Prof. Dr. Melanie Kappelmann-Fenzl

Lehrgebiet: Angewandte Biowissenschaften

  • Humangenetik
  • Molekularbiologie
  • Hochdurchsatzsequenzierung (Omics)
  • Biomedizinische Datenanalyse

Fakultät Angewandte Informatik

Professorinnen und Professoren

Professorin

  • Studiengangskoordintion Bachelor Bioinformatik und Master Life Science Informatics
  • Studienfachberatung Bachelor Bioinformatik und Master Life Science Informatics

K 008

0991/3615-473

Sprechzeiten

Nach Vereinbarung.

Forschungsgruppe Bioinformatik: https://www.th-deg.de/fg-bioinformatik

Sortierung:
Zeitschriftenartikel
  • B. Spangler
  • Melanie Kappelmann-Fenzl
  • B. Schittek
  • S. Meierjohann
  • L. Vardimon
  • A.-K. Bosserhoff
  • S. Kuphal

ETS‐1/RhoC signaling regulates the transcription factor c‐Jun in melanoma.

In: International Journal of Cancer (vol. 130) , pg. 2801-2811

(2012)

DOI: 10.1002/ijc.26277

Abstract anzeigen

Recently, we discovered that the loss of E‐cadherin induces c‐Jun protein expression, which is a member of the AP‐1 transcription factor family and a key player in the processes of cell proliferation and tumor development and also found in elevated levels in melanomas. Notably, the mRNA level of c‐Jun was not affected, suggesting that c‐Jun is regulated at post‐transcriptional level. Here, we present data that suggest that the dynamic cytoskeletal network, linked to E‐cadherin, is involved in the regulation of the c‐Jun protein and transcriptional activity. In a signaling cascade, the loss of E‐cadherin activates the transcriptional regulator ETS‐1 and consequently leads to the induction of RhoC expression that stabilizes c‐Jun in melanoma. The link between RhoC and c‐Jun seems to be indirect via the cytoskeleton. We conclude that the loss of E‐cadherin mediated cell‐adhesion induces c‐Jun protein expression in a multistep process, offering several possibilities for therapeutic intervention.
Zeitschriftenartikel
  • Melanie Kappelmann-Fenzl
  • S. Kuphal
  • G. Meister
  • L. Vardimon
  • A.-K. Bosserhoff

MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression.

In: Oncogene (vol. 32) , pg. 2984-2991

(2013)

DOI: 10.1038/onc.2012.307

Abstract anzeigen

A fundamental event in the development and progression of malignant melanoma is the deregulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of tumor progression in melanoma and thus the most important member of the AP-1 transcription factor family for this disease. Interestingly, we revealed that c-Jun expression was regulated on the post-transcriptional level and therefore speculated that miRNAs could be involved in c-Jun regulation. We determined seed sequences for miR-125b and miR-527 in the coding region of c-Jun mRNA that hints at the direct involvement of miRNA-dependent regulation on the protein level. We found that the expression of miR-125b was significantly reduced in malignant melanoma cell lines and tissue samples compared with melanocytes, whereas miR-527 remained unchanged. In further functional experiments, treatment of melanoma cells with pre-miR-125b resulted in strong suppression of cellular proliferation and migration, supporting the role of miR-125b in melanoma. In addition, transfection of pre-miR-125b led to strong downregulation of c-Jun protein but not mRNA expression in melanoma cells. Luciferase assays using reporter plasmids containing the miR-125b seed sequence in the luciferase coding region confirmed the direct interaction with miR-125b. Furthermore, immunoprecipitation of Ago-2 revealed that c-Jun mRNA accumulated in the RNA-induced silencing complex after pre-miR-125b transfection in melanoma cells. In summary, we identified an important role for miR-125b in malignant melanoma. Moreover, we demonstrated post-transcriptional regulation of c-Jun by this miRNA and showed that c-Jun is a main mediator of the effects of miR-125b on melanoma cells.
Hochschulschrift
  • Melanie Kappelmann-Fenzl

Regulation und Funktion des Trankriptionsfaktors c-Jun im malignen Melanom.

Universität Regensburg, Regensburg. Naturwissenschaftliche Fakultät für Biologie und vorklinische Medizin

(2014)

Zeitschriftenartikel
  • S. Hagemann
  • L. Stöger
  • Melanie Kappelmann-Fenzl
  • I. Hassl
  • A. Ellinger
  • B. Velimirov

DNA-bearing membrane vesicles produced by Ahrensia kielensis and Pseudoalteromonas marina.

In: Journal of Basic Microbiology (vol. 54) , pg. 1062-1072

(2014)

DOI: 10.1002/jobm.201300376

Abstract anzeigen

Outer membrane vesicles (OMVs) derived from the alphaproteobacterium Ahrensia kielensis and from Pseudoalteromonas marina, a gammaproteobacterium, were sampled from liquid cultures in order to extract the MV-associated DNA, establish a shotgun library, and sequence randomly chosen clones to determine the origins of their DNA. We show that OMVs from A. kielensis and from P. marina both harbour DNA larger than 20 or 30 kbp. Transmission electron microscopical inspection of OMVs of A. kielensis and P. marina showed two types of vesicles: bilayered OMVs with a diameter between 30 and 250 nm and double bilayered OMVs ranging between 80 and 200 nm. Bilayered OMVs are either characterized by the presence of a large electron-dense substance or are elctron translucent. Double bilayered OMVs contained an electron dense substance in the core region surrounded by the second bilayer. 30,094 bp of the genome from OMV of A. kielensis and 45,981 bp of that from P. marina were sequenced. The results indicated that all sequences were single copy and that all sequences, with one exception, were similar to prokaryotic sequences, inserted viral sequences were not detected.
Zeitschriftenartikel
  • P. Schummer
  • S. Kuphal
  • L. Vardimon
  • A.-K. Bosserhoff
  • Melanie Kappelmann-Fenzl

Specific c-Jun target genes in malignant melanoma.

In: Cancer Biology & Therapy (vol. 17) , pg. 486-497

(2016)

DOI: 10.1080/15384047.2016.1156264

Abstract anzeigen

A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.
Zeitschriftenartikel
  • Melanie Kappelmann-Fenzl
  • S. Kuphal
  • R. Krupar
  • D. Schadendorf
  • V. Umansky
  • L. Vardimon
  • C. Hellerbrand
  • A.-K. Bosserhoff

Complex Formation with Monomeric α-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun's Nuclear Translocation and Activity.

In: Cancers (vol. 11) , pg. 1-12

(2019)

DOI: 10.3390/cancers11111806

Abstract anzeigen

Microtubules are highly dynamic structures, which consist of α- and β-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun is a central driver of melanoma development and progression. Here, we identify the microtubule network as a main regulator of c-Jun activity. Monomeric α-tubulin fosters c-Jun protein stability by protein-protein interaction. In addition, this complex formation is necessary for c-Jun's nuclear localization sequence binding to importin 13, and consequent nuclear import and activity of c-Jun. A reduction in monomeric α-tubulin levels by treatment with the chemotherapeutic paclitaxel resulted in a decline in the nuclear accumulation of c-Jun in melanoma cells in an experimental murine model and in patients' tissues. These findings add important knowledge to the mechanism of the action of microtubule-targeting drugs and indicate the newly discovered regulation of c-Jun by the microtubule cytoskeleton as a novel therapeutic target for melanoma and potentially also other types of cancer.
Vortrag
  • Melanie Kappelmann-Fenzl
  • C. Gebhardt
  • A. Matthies
  • S. Kuphal
  • M. Rehli
  • A.-K. Bosserhoff

C-Jun drives melanoma progression in PTEN wild type melanoma cells.

  • Deutsches Krebsforschungszentrum.

Heidelberg 16.-19.09.2019.

(2019)

Beitrag in Sammelwerk/Tagungsband
  • M. Heppt
  • A. Wessely
  • E. Hornig
  • C. Kammerbauer
  • S. Graf
  • R. Besch
  • L. French
  • S. Kuphal
  • Melanie Kappelmann-Fenzl
  • A.-K. Bosserhoff
  • C. Bosserhoff
  • C. Berking

Brn3a expression is epigenetically controlled by HDAC2 in melanocytes and melanoma.

pg. P.196

(2021)

Beitrag in Sammelwerk/Tagungsband
  • A.-K. Bosserhoff
  • Melanie Kappelmann-Fenzl

Next Generation Sequencing (NGS): What Can Be Sequenced?.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 1-15

DOI: 10.1007/978-3-030-62490-3_1

(2021)

Beitrag in Sammelwerk/Tagungsband
  • Melanie Kappelmann-Fenzl

NGS Data.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 79-104

DOI: 10.1007/978-3-030-62490-3_7

(2021)

Beitrag in Sammelwerk/Tagungsband
  • Melanie Kappelmann-Fenzl

Reference Genome.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 105-109

DOI: 10.1007/978-3-030-62490-3_8

(2021)

Zeitschriftenartikel
  • M. Fuentes-Chandía
  • A. Vierling
  • Melanie Kappelmann-Fenzl
  • M. Monavari
  • G. Letort
  • L. Höne
  • B. Parma
  • S. Antara
  • Ö. Ertekin
  • R. Palmisano
  • M. Dong
  • K. Böpple
  • A. Boccaccini
  • P. Ceppi
  • A.-K. Bosserhoff
  • A. Leal-Egaña

3D Spheroids Versus 3D Tumor-Like Microcapsules: Confinement and Mechanical Stress May Lead to the Expression of Malignant Responses in Cancer Cells.

In: Advanced Biology , pg. e2000349

(2021)

DOI: 10.1002/adbi.202000349

Abstract anzeigen

As 2D surfaces fail to resemble the tumoral milieu, current discussions are focused on which 3D cell culture strategy may better lead the cells to express in vitro most of the malignant hints described in vivo. In this study, this question is assessed by analyzing the full genetic profile of MCF7 cells cultured either as 3D spheroids-considered as "gold standard" for in vitro cancer research- or immobilized in 3D tumor-like microcapsules, by RNA-Seq and transcriptomic methods, allowing to discriminate at big-data scale, which in vitro strategy can better resemble most of the malignant features described in neoplastic diseases. The results clearly show that mechanical stress, rather than 3D morphology only, stimulates most of the biological processes involved in cancer pathogenicity, such as cytoskeletal organization, migration, and stemness. Furthermore, cells entrapped in hydrogel-based scaffolds are likely expressing other physiological hints described in malignancy, such as the upregulated expression of metalloproteinases or the resistance to anticancer drugs, among others. According to the knowledge, this study represents the first attempt to answer which 3D experimental system can better mimic the neoplastic architecture in vitro, emphasizing the relevance of confinement in cancer pathogenicity, which can be easily achieved by using hydrogel-based matrices.
Beitrag in Sammelwerk/Tagungsband
  • Melanie Kappelmann-Fenzl

Alignment.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 111-122

DOI: 10.1007/978-3-030-62490-3_9

(2021)

Zeitschriftenartikel
  • N. Rachinger
  • Stefan Fischer
  • I. Böhme
  • L. Linck-Paulus
  • S. Kuphal
  • Melanie Kappelmann-Fenzl
  • A.-K. Bosserhoff

Loss of Gene Information: Discrepancies between RNA Sequencing, cDNA Microarray, and qRT-PCR.

In: International Journal of Molecular Sciences (vol. 22) , pg. 9349

(2021)

DOI: 10.3390/ijms22179349

Abstract anzeigen

Molecular analyses of normal and diseased cells give insight into changes in gene expression and help in understanding the background of pathophysiological processes. Years after cDNA microarrays were established in research, RNA sequencing (RNA-seq) became a key method of quantitatively measuring the transcriptome. In this study, we compared the detection of genes by each of the transcriptome analysis methods: cDNA array, quantitative RT-PCR, and RNA-seq. As expected, we found differences in the gene expression profiles of the aforementioned techniques. Here, we present selected genes that exemplarily demonstrate the observed differences and calculations to reveal that a strong RNA secondary structure, as well as sample preparation, can affect RNA-seq. In summary, this study addresses an important issue with a strong impact on gene expression analysis in general. Therefore, we suggest that these findings need to be considered when dealing with data from transcriptome analyses.
Beitrag in Sammelwerk/Tagungsband
  • M. Eisele
  • Melanie Kappelmann-Fenzl

NGS Technologies.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 47-58

DOI: 10.1007/978-3-030-62490-3_4

(2021)

Beitrag in Sammelwerk/Tagungsband
  • Melanie Kappelmann-Fenzl

Library Construction for NGS.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 39-45

DOI: 10.1007/978-3-030-62490-3_3

(2021)

Beitrag in Sammelwerk/Tagungsband
  • Melanie Kappelmann-Fenzl

Computer Setup.

  • In:
  • Melanie Kappelmann-Fenzl

Cham, Switzerland: Springer Nature Switzerland AG pg. 59-69

DOI: 10.1007/978-3-030-62490-3_5

(2021)

Vortrag
  • S. Ranganathan
  • D. Riewe
  • A. Feiner
  • S. Steiner
  • Melanie Kappelmann-Fenzl
  • S. Fischer

De novo assembly of Humulus lupulus transcriptome comparing different bioinformatic tools. Posterpräsentation.

Online 06.-08.09.2021.

Zeitschriftenartikel
  • Ö. Ertekin
  • M. Monavari
  • R. Krüger
  • M. Fuentes-Chandía
  • B. Parma
  • G. Letort
  • P. Tripal
  • A. Boccaccini
  • A.-K. Bosserhoff
  • P. Ceppi
  • Melanie Kappelmann-Fenzl
  • A. Leal-Egaña

3D hydrogel-based microcapsules as an in vitro model to study tumorigenicity, cell migration and drug resistance.

In: Acta Biomaterialia

(2022)

DOI: 10.1016/j.actbio.2022.02.010

Abstract anzeigen

In this work, we analyzed the reliability of alginate-gelatin microcapsules as artificial tumor model. These tumor-like scaffolds are characterized by their composition and stiffness (∼25 kPa), and their capability to restrict -but not hinder- cell migration, proliferation and release from confinement. Hydrogel-based microcapsules were initially utilized to detect differences in mechano-sensitivity between MCF7 and MDA-MB-231 breast cancer cells, and the endothelial cell line EA.hy926. Additionally, we used RNA-seq and transcriptomic methods to determine how the culture strategy (i.e. 2D v/s 3D) may pre-set the expression of genes involved in multidrug resistance, being then validated by performing cytotoxicological tests and assays of cell morphology. Our results show that both breast cancer cells can generate elongated multicellular spheroids inside the microcapsules, prior being released (mimicking intravasation stages), a behavior which was not observed in endothelial cells. Further, we demonstrate that cells isolated from 3D scaffolds show resistance to cisplatin, a process which seems to be strongly influenced by mechanical stress, instead of hypoxia. We finally discuss the role played by aneuploidy in malignancy and resistance to anticancer drugs, based on the increased number of polynucleated cells found within these microcapsules. Overall, our outcomes demonstrate that alginate-gelatin microcapsules represent a simple, yet very accurate tumor-like model, enabling us to mimic the most relevant malignant hints described in vivo, suggesting that confinement and mechanical stress need to be considered when studying pathogenicity and drug resistance of cancer cells in vitro. STATEMENT OF SIGNIFICANCE: In this work, we analyzed the reliability of alginate-gelatin microcapsules as an artificial tumor model. These scaffolds are characterized by their composition, elastic properties, and their ability to restrict cell migration, proliferation, and release from confinement. Our results demonstrate four novel outcomes: (i) studying cell migration and proliferation in 3D enabled discrimination between malignant and non-pathogenic cells, (ii) studying the cell morphology of cancer aggregates entrapped in alginate-gelatin microcapsules enabled determination of malignancy degree in vitro, (iii) determination that confinement and mechanical stress, instead of hypoxia, are required to generate clones resistant to anticancer drugs (i.e. cisplatin), and (iv) evidence that resistance to anticancer drugs could be due to the presence of polynucleated cells localized inside polymer-based artificial tumors.
Zeitschriftenartikel
  • L. Linck-Paulus
  • T. Meißgeier
  • K. Pieger
  • A. Horn
  • A. Matthies
  • Stefan Fischer
  • G. Meister
  • H. Sticht
  • Melanie Kappelmann-Fenzl
  • A. Bosserhoff

A previously unknown Argonaute 2 variant positively modulates the viability of melanoma cells.

In: Cellular and Molecular Life Sciences : CMLS (vol. 79) , pg. 475

(2022)

DOI: 10.1007/s00018-022-04496-8

Abstract anzeigen

In malignant melanoma, a highly aggressive form of skin cancer, many microRNAs are aberrantly expressed contributing to tumorigenesis and progression. Further, deregulation of microRNA processing enzymes, like the miRNA-binding protein Argonaute 2, significantly impacts microRNA function. This study characterizes a novel splice variant of Argonaut 2, AGO2-ex1/3. AGO2-ex1/3 is substantially expressed in different melanoma cell lines and patient-derived tissue samples. It is a mature mRNA, which is translated into an N-terminally truncated Argonaute 2 protein form. Molecular dynamics simulations show that the PAZ, MID, and PIWI domain largely retain their structure in AGO2-ex1/3 and that the truncation of the N-terminus leads to an increased interdomain flexibility. Expression of AGO2-ex1/3 provides a survival advantage for melanoma cells while the knockdown causes significantly reduced proliferation and increases apoptosis. RNA-sequencing revealed that in cells lacking AGO2-ex1/3 expression many miRNA target genes are deregulated, implicating a considerable role of AGO2-ex1/3 for miRNA function. This study inaugurates insights into an important role of a so far unknown splice variant of Argonaute 2 for the miRNA pathway as well as the mechanisms which drive growth and survival of melanoma cells. This knowledge provides the basis for potential new promising therapeutic targets focusing on small RNA-mediated gene regulation in melanoma.
Zeitschriftenartikel
  • I. Stüfchen
  • R. Beckervordersandforth
  • Stefan Fischer
  • Melanie Kappelmann-Fenzl
  • A.-K. Bosserhoff
  • F. Beyer

Two novel CreERT2 transgenic mouse lines to study melanocytic cells in vivo.

In: Pigment Cell & Melanoma Research , pg. 1-9

(2022)

DOI: 10.1111/pcmr.13061

Abstract anzeigen

The skin of adult mammals protects from radiation, physical and chemical insults. While melanocytes and melanocyte-producing stem cells contribute to proper skin function in healthy organisms, dysfunction of these cells can lead to the generation of malignant melanoma-the deadliest type of skin cancer. Addressing cells of the melanocyte lineage in vivo represents a prerequisite for the understanding of melanoma on cellular level and the development of preventive and treatment strategies. Here, the inducible Cre-loxP-system has emerged as a promising tool to specifically target, monitor, and modulate cells in adult mice. Re-analysis of existing sequencing data sets of melanocytic cells revealed that genes with a known function in neural cells, including neural stem cells (Aldh1L1 and Nestin), are also expressed in melanocytic cells. Therefore, in this study, we explored whether the promoter activity of Nestin and Aldh1L1 can serve to target cells of the melanocyte lineage using the inducible CreERT2 -loxP-system. Using an immunohistochemical approach and different time points of analysis, we were able to map the melanocytic fate of recombined stem cells in the adult hair follicle of Nestin-CreERT2 and Aldh1L1-CreERT2 transgenic mice. Thus, we here present two new mouse models and propose their use to study and putatively modulate adult melanocytic cells in vivo.
Zeitschriftenartikel
  • L. Linck-Paulus
  • A. Horn
  • A. Matthies
  • Stefan Fischer
  • G. Meister
  • H. Sticht
  • Melanie Kappelmann-Fenzl
  • A. Bosserhoff

Eine neue Spleißvariante von Argonaut 2 beeinflusst microRNA-Zielgene und die Zellviabilität von Melanomzellen. ePoster zum 32. Deutschen Hautkrebskongress (ADO) in Hannover.

In: JDDG: Journal der Deutschen Dermatologischen Gesellschaft (vol. 20) , pg. 28-114

(2022)

DOI: 10.1111/ddg.14901

Zeitschriftenartikel
  • M. Heppt
  • A. Wessely
  • E. Hornig
  • C. Kammerbauer
  • S. Graf
  • R. Besch
  • L. French
  • A. Matthies
  • S. Kuphal
  • Melanie Kappelmann-Fenzl
  • A.-K. Bosserhoff
  • C. Berking

HDAC2 Is Involved in the Regulation of BRN3A in Melanocytes and Melanoma.

In: International Journal of Molecular Sciences (vol. 23) , pg. 849

(2022)

DOI: 10.3390/ijms23020849

Abstract anzeigen

The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
Beitrag in Sammelwerk/Tagungsband
  • S. Schmidt
  • Stefan Fischer
  • R. Schmid
  • A. Arkudas
  • A. Kengelbach-Weigand
  • Melanie Kappelmann-Fenzl
  • A. Bosserhoff

Molecular analysis of tumor dormancy in a 3D printed melanoma model.

pg. 176

(2022)

Zeitschriftenartikel
  • M. Schott
  • Melanie Kappelmann-Fenzl
  • Stefan Fischer
  • M. Fernandez-Barrena
  • A. Pineda-Lucena
  • M. Ávila
  • S. Kuphal
  • A.-K. Bosserhoff

Impact of CYLD on chromatin structure and histone methylation in malignant melanoma.

In: International Journal of Molecular Medicine (vol. 49)

(2022)

DOI: 10.3892/ijmm.2022.5122

Abstract anzeigen

The tumor suppressive role of CYLD lysine 63 deubiquitinase (CYLD) is known in melanoma. To the best of our knowledge, however, the precise mechanism underlying the tumor suppressive function of CYLD has yet to be clarified. In the present study, a novel melanoma mouse model was generated, which revealed accelerated tumor growth in Cyld‑knockout (Cyld‑/‑) compared with Cyld‑wild‑type (Cyld+/+) mice. To determine the underlying molecular mechanism, mutation analysis of primary tumor‑derived cell lines from Cyld+/+ and Cyld‑/‑ mice was performed using RNA sequencing data. Variant calling revealed no common mutations in Cyld‑/‑ compared with Cyld+/+ cells. Thus, the epigenetic processes influencing development and progression of melanoma were investigated. Initial analysis of expression pattern of known hypermethylated genes in melanoma (suppressor of cytokine signalling, methylthioadenosine phosphorylase, cadherin 1) in the presence or absence of 5'‑Aza‑deoxyctidine treatment revealed that CYLD does not play a key role in DNA methylation. Chromatin accessibility and histone H3 modification assay uncovered a role of CYLD in the formation of chromatin structure. Subsequent inhibitor experiments confirmed the effect of CYLD on H3K9me2 level associated with heterochromatin. Furthermore, enhanced H3K9 dimethylation in Cyld‑/‑ melanoma cells was associated with upregulation of euchromatic histone lysine methyltransferase 2 (EHMT2). Moreover, the specific inhibitor of EHMT2, CM272, resulted in decreased proliferation and relaxation of compact chromatin in Cyld‑deficient melanoma cells. These results reveal a novel role of CYLD in histone methylation and chromatin packaging.
Vortrag
  • Melanie Kappelmann-Fenzl

Bioinformatische Analyse molekularer Mechanismen der AP-1 Transkriptionsaktivität und deren funktioneller Bedeutung im malignen Melanom.

  • Technische Hochschule Deggendorf.

Technische Hochschule Deggendorf 23.06.2022.

(2022)

Vortrag
  • Stefan Fischer
  • S. Schmidt
  • Melanie Kappelmann-Fenzl
  • R. Schmid
  • L. Lämmerhirt
  • L. Fischer
  • S. Schrüfer
  • I. Thievessen
  • D. Schubert
  • A. Matthies
  • R. Detsch
  • A. Boccaccini
  • A. Arkudas
  • A. Kengelbach-Weigand
  • A. Bosserhoff

Bioinformatic analysis of different 2D and 3D culture conditions of an established melanoma cell model.

  • German Society for Biochemistry and Molecular Biology.

Düsseldorf 14.-16.09.2022.

(2022)

Vortrag
  • Melanie Kappelmann-Fenzl

Mutationen & Co. KG.

Deggendorf 11.05.2023.

(2023)

Zeitschriftenartikel
  • L. Lämmerhirt
  • Melanie Kappelmann-Fenzl
  • Stefan Fischer
  • P. Meier
  • S. Staebler
  • S. Kuphal
  • A. Bosserhoff

Loss of miR-101-3p in melanoma stabilizes genomic integrity, leading to cell death prevention.

In: Cellular & Molecular Biology Letters (vol. 29) , pg. 29

(2024)

DOI: 10.1186/s11658-024-00552-2

Abstract anzeigen

Malignant melanoma remains the most lethal form of skin cancer, exhibiting poor prognosis after forming distant metastasis. Owing to their potential tumor-suppressive properties by regulating oncogenes and tumor suppressor genes, microRNAs are important player in melanoma development and progression. We defined the loss of miR-101-3p expression in melanoma cells compared with melanocytes and melanoblast-related cells as an early event in tumor development and aimed to understand the tumor suppressive role of miR-101-3p and its regulation of important cellular processes. Reexpression of miR-101-3p resulted in inhibition of proliferation, increase in DNA damage, and induction of apoptosis. We further determined the nuclear structure protein Lamin B1, which influences nuclear processes and heterochromatin structure, ATRX, CASP3, and PARP as an important direct target of miR-101-3p. RNA sequencing and differential gene expression analysis after miR-101-3p reexpression supported our findings and the importance of loss of mir-101-3p for melanoma progression. The validated functional effects are related to genomic instability, as recent studies suggest miRNAs plays a key role in mediating this cellular process. Therefore, we concluded that miR-101-3p reexpression increases the genomic instability, leading to irreversible DNA damage, which leads to apoptosis induction. Our findings suggest that the loss of miR-101-3p in melanoma serves as an early event in melanoma progression by influencing the genomic integrity to maintain the increased bioenergetic demand.
Zeitschriftenartikel
  • S. Staebler
  • U. Rottensteiner-Brandl
  • Z. El Ahmad
  • Melanie Kappelmann-Fenzl
  • A. Arkudas
  • A. Kengelbach-Weigand
  • A. Bosserhoff
  • S. Schmidt

Transcription factor activating enhancer-binding protein 2ε (AP2ε) modulates phenotypic plasticity and progression of malignant melanoma.

In: Cell Death & Disease (vol. 15) , pg. 351

(2024)

DOI: 10.1038/s41419-024-06733-3

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Malignant melanoma, the most aggressive form of skin cancer, is often incurable once metastatic dissemination of cancer cells to distant organs has occurred. We investigated the role of Transcription Factor Activating Enhancer-Binding Protein 2ε (AP2ε) in the progression of metastatic melanoma. Here, we observed that AP2ε is a potent activator of metastasis and newly revealed AP2ε to be an important player in melanoma plasticity. High levels of AP2ε lead to worsened prognosis of melanoma patients. Using a transgenic melanoma mouse model with a specific loss of AP2ε expression, we confirmed the impact of AP2ε to modulate the dynamic switch from a migratory to a proliferative phenotype. AP2ε deficient melanoma cells show a severely reduced migratory potential in vitro and reduced metastatic behavior in vivo. Consistently, we revealed increased activity of AP2ε in quiescent and migratory cells compared to heterogeneously proliferating cells in bioprinted 3D models. In conclusion, these findings disclose a yet-unknown role of AP2ε in maintaining plasticity and migration in malignant melanoma cells.
Zeitschriftenartikel
  • V. Kluge
  • Melanie Kappelmann-Fenzl
  • Stefan Fischer
  • T. Zimmermann
  • M. Pommer
  • S. Kuphal
  • A.-K. Bosserhoff

Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence.

In: Cell Death & Disease (vol. 15) , pg. 166

(2024)

DOI: 10.1038/s41419-024-06550-8

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Oncogene-induced senescence (OIS) is an important process that suppresses tumor development, but the molecular mechanisms of OIS are still under investigation. It is known that BRAFV600E-mutated melanocytes can overcome OIS and develop melanoma, but the underlying mechanism is largely unknown. Using an established OIS model of primary melanocytes transduced with BRAFV600E, YAP activity was shown to be induced in OIS as well as in melanoma cells compared to that in normal epidermal melanocytes. This led to the assumption that YAP activation itself is not a factor involved in the disruption of OIS. However, its role and interaction partners potentially change. As Wnt molecules are known to be important in melanoma progression, these molecules were the focus of subsequent studies. Interestingly, activation of Wnt signaling using AMBMP resulted in a disruption of OIS in BRAFV600E-transduced melanocytes. Furthermore, depletion of Wnt6, Wnt10b or β-catenin expression in melanoma cells resulted in the induction of senescence. Given that melanoma cells do not exhibit canonical Wnt/β-catenin activity, alternative β-catenin signaling pathways may disrupt OIS. Here, we discovered that β-catenin is an interaction partner of YAP on DNA in melanoma cells. Furthermore, the β-catenin-YAP interaction changed the gene expression pattern from senescence-stabilizing genes to tumor-supportive genes. This switch is caused by transcriptional coactivation via the LEF1/TEAD interaction. The target genes with binding sites for LEF1 and TEAD are involved in rRNA processing and are associated with poor prognosis in melanoma patients. This study revealed that an alternative YAP-Wnt signaling axis is an essential molecular mechanism leading to OIS disruption in melanocytes.

Projekte

Molekulare Mechanismen unterschiedlicher Transkriptionsaktivität der AP-1-Faktoren c-Jun, Fra-1 und ATF-2, und deren funktionelle Bedeutung im malignen Melanom (DFG-Projekt)

Labore

Labor für Translationale Biomedizin (Raum D 109)

Sonstiges

Kooperationen:

  • Abteilung Molekularpathologie des Institutes für Pathologie und Zytologie am DONAUISAR KLINIKUM Deggendorf (Dr. Hamberger, Dr. Mohren)
  • BioVariance GmbH, Dr. Josef Scheiber

Mitgliedschaften:

  • Gesellschaft Biochemie und Molekularbiologie e.V. (GBM)
  • Fachgruppe Bioinformatik (FaBi)
  • The Society for Melanoma Research (SMR)
  • Hochschullehrerbund - Bundesvereinigung e.V. (hlb)
  • BayWISS-Kolleg Gesundheit