The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma.
Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.
Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Rajeev K
RK
Boregowda
Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Daniel J
DJ
Medina
Cancer Research UK Beatson Institute, Glasgow, G61 1BD Scotland, UK.
Elke
E
Markert
Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Michael A
MA
Bryan
Center for Biomedical Imaging & Informatics, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.|Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Wenjin
W
Chen
Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Suzie
S
Chen
Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA.
Anna
A
Rabkin
Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Michael J
MJ
Vido
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
Samuel I
SI
Gunderson
Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Marina
M
Chekmareva
Center for Biomedical Imaging & Informatics, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.|Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
David J
DJ
Foran
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.|Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Ahmed
A
Lasfar
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
James S
JS
Goydos
Division of Surgical Oncology, Department of Surgery, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
Karine A
KA
Cohen-Solal
D019898:Autocrine Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D020794:Receptor Protein-Tyrosine Kinases
RUNX2; melanoma; receptor tyrosine kinase; resistance to targeted therapy; transcription factor