TY - JOUR
T1 - New insights into the runt domain of RUNX2 in melanoma cell proliferation and migration
AU - Deiana, Michela
AU - Carbonare, Luca Dalle
AU - Serena, Michela
AU - Cheri, Samuele
AU - Parolini, Francesca
AU - Gandini, Alberto
AU - Marchetto, Giulia
AU - Innamorati, Giulio
AU - Manfredi, Marcello
AU - Marengo, Emilio
AU - Brandi, Jessica
AU - Cecconi, Daniela
AU - Mori, Antonio
AU - Mina, Maria Mihaela
AU - Antoniazzi, Franco
AU - Mottes, Monica
AU - Tiso, Natascia
AU - Malerba, Giovanni
AU - Zipeto, Donato
AU - Valenti, Maria Teresa
N1 - Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/11/20
Y1 - 2018/11/20
N2 - The mortality rate for malignant melanoma (MM) is very high, since it is highly invasive and resistant to chemotherapeutic treatments. The modulation of some transcription factors affects cellular processes in MM. In particular, a higher expression of the osteogenic master gene RUNX2 has been reported in melanoma cells, compared to normal melanocytes. By analyzing public databases for recurrent RUNX2 genetic and epigenetic modifications in melanoma, we found that the most common RUNX2 genetic alteration that exists in transcription upregulation is, followed by genomic amplification, nucleotide substitution and multiple changes. Additionally, altered RUNX2 is involved in unchecked pathways promoting tumor progression, Epithelial Mesenchymal Transition (EMT), and metastasis. In order to investigate further the role of RUNX2 in melanoma development and to identify a therapeutic target, we applied the CRISPR/Cas9 technique to explore the role of the RUNT domain of RUNX2 in a melanoma cell line. RUNT-deleted cells showed reduced proliferation, increased apoptosis, and reduced EMT features, suggesting the involvement of the RUNT domain in different pathways. In addition, del-RUNT cells showed a downregulation of genes involved in migration ability. In an in vivo zebrafish model, we observed that wild-type melanoma cells migrated in 81% of transplanted fishes, while del-RUNT cells migrated in 58%. All these findings strongly suggest the involvement of the RUNT domain in melanoma metastasis and cell migration and indicate RUNX2 as a prospective target in MM therapy.
AB - The mortality rate for malignant melanoma (MM) is very high, since it is highly invasive and resistant to chemotherapeutic treatments. The modulation of some transcription factors affects cellular processes in MM. In particular, a higher expression of the osteogenic master gene RUNX2 has been reported in melanoma cells, compared to normal melanocytes. By analyzing public databases for recurrent RUNX2 genetic and epigenetic modifications in melanoma, we found that the most common RUNX2 genetic alteration that exists in transcription upregulation is, followed by genomic amplification, nucleotide substitution and multiple changes. Additionally, altered RUNX2 is involved in unchecked pathways promoting tumor progression, Epithelial Mesenchymal Transition (EMT), and metastasis. In order to investigate further the role of RUNX2 in melanoma development and to identify a therapeutic target, we applied the CRISPR/Cas9 technique to explore the role of the RUNT domain of RUNX2 in a melanoma cell line. RUNT-deleted cells showed reduced proliferation, increased apoptosis, and reduced EMT features, suggesting the involvement of the RUNT domain in different pathways. In addition, del-RUNT cells showed a downregulation of genes involved in migration ability. In an in vivo zebrafish model, we observed that wild-type melanoma cells migrated in 81% of transplanted fishes, while del-RUNT cells migrated in 58%. All these findings strongly suggest the involvement of the RUNT domain in melanoma metastasis and cell migration and indicate RUNX2 as a prospective target in MM therapy.
KW - CRISPR/Cas9
KW - Melanoma
KW - RUNT
KW - RUNX2
UR - http://www.scopus.com/inward/record.url?scp=85066847988&partnerID=8YFLogxK
U2 - 10.3390/cells7110220
DO - 10.3390/cells7110220
M3 - Article
SN - 2073-4409
VL - 7
JO - Cells
JF - Cells
IS - 11
M1 - 220
ER -