Oncotarget

Research Papers:

MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth

Christina Wilms, Carsten M. Kroeger, Adelheid V. Hainzl, Ishani Banik, Clara Bruno, Ioanna Krikki, Vida Farsam, Meinhard Wlaschek and Martina V. Gatzka _

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Oncotarget. 2017; 8:67287-67299. https://doi.org/10.18632/oncotarget.18617

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Abstract

Christina Wilms1,*, Carsten M. Kroeger1,*, Adelheid V. Hainzl1, Ishani Banik1,2, Clara Bruno1,3, Ioanna Krikki1, Vida Farsam1, Meinhard Wlaschek1 and Martina V. Gatzka1

1Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany

2ETH, 8092 Zurich, Switzerland

3Department of Neurology, Ulm University, 89081 Ulm, Germany

*These authors have contributed equally to this work

Correspondence to:

Martina V. Gatzka, email: martina.gatzka@uni-ulm.de

Keywords: epigenetics, melanoma, pigmentation, transcriptional regulation, UV-radiation

Received: December 22, 2016     Accepted: May 31, 2017     Published: June 27, 2017

ABSTRACT

Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments. Based on the identification of alterations in skin pigmentation and melanocyte specification in Mysm1-deficient mice, we hypothesized that MYSM1 may be involved in melanoma formation. In human melanoma samples, expression of MYSM1 was increased compared with normal skin melanocytes and nevi and co-localized with melanocyte markers such as Melan-A and c-KIT. Similarly, in melanoma cell lines A375 and SK-MEL-28 and in murine skin, expression of the deubiquitinase was detectable at the mRNA and protein level that was inducible by growth factor signals and UVB exposure, respectively. Upon stable silencing of MYSM1 in A375 and SK-MEL-28 melanoma cells by lentivirally-mediated shRNA expression, survival and proliferation were significantly reduced in five MYSM1 shRNA cell lines analyzed compared with control cells. In addition, MYSM1-silenced melanoma cells proliferated less well in softagar assays. In context with our finding that MYSM1 bound to the c-MET promoter region in close vicinity to PAX3 in melanoma cells, our data indicate that MYSM1 is an epigenetic regulator of melanoma growth and potentially promising new target for tumor therapy.


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