The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma

Boregowda, R. K. et al. (2016) The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget, 7(20), pp. 29689-29707. (doi: 10.18632/oncotarget.8822) (PMID:27102439)

Abstract

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.

• Item Type: Articles
• Additional Information: The present work was supported by a Research Scholar Grant from the American Cancer Society 116683-RSG-09-087-01-TBE and an Elizabeth and Barets O. Benjamin Foundation Career Development Award for Women in Cancer Research (K.C.S.) and a grant from the National Cancer Institute 1RO1CA149627-01 (J. G.). This research was funded, in part, by grants from the National Institute of Health through contracts 5R01CA156386-09 and 5R01CA161375-03 from the National Cancer Institute; and contracts 5R01LM011119-04 and 5R01LM009239-06 from the National Library of Medicine (D.F.). This research was funded, in part, by a NCI/NIH grant R21-CA191622 (S.I.G.). M.V. is supported by the National Institute of Health grant R01CA182635 (A. Aplin).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Markert, Dr Elke
• Authors: Boregowda, R. K., Medina, D. J., Markert, E., Bryan, M. A., Chen, W., Chen, S., Rabkin, A., Vido, M. J., Gunderson, S. I., Chekmareva, M., Foran, D. J., Lasfar, A., Goydos, J. S., and Cohen-Solal, K. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Copyright Holders: Copyright © 2016 Impact Journals, LLC
• First Published: First published in Oncotarget 7(20): 29689-29707
• Publisher Policy: Reproduced under a Creative Commons License