High levels of Hdmx promote cell growth in a subset of uveal melanomas

Job de Lange, Amina Fas Teunisse, Matty Verlaan-de Vries, Kirsten Lodder, Suzanne Lam, Gregorius Pm Luyten, Federico Bernal, Martine J Jager, Aart G Jochemsen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The p53 tumor suppressor pathway is inactivated in cancer either via direct mutation or via deregulation of upstream regulators or downstream effectors. P53 mutations are rare in uveal melanoma. Here we investigated the role of the p53 inhibitor Hdmx in uveal melanoma. We found Hdmx over-expression in a subset of uveal melanoma cell lines and fresh-frozen tumor samples. Hdmx depletion resulted in cell-line dependent growth inhibition, apparently correlating with differential Hdm2 levels. Surprisingly, p53 knockdown hardly rescued cell cycle arrest and apoptosis induction upon Hdmx knockdown, whereas it effectively prevented growth suppression induced by the potent p53 activator Nutlin-3. In addition, two compounds inhibiting Hdmx function or expression, SAH-p53-8 and XI-011, also elicited a growth inhibitory effect in a partly p53-independent manner. These findings suggest a novel, growth-promoting function of Hdmx that does not rely on its ability to inhibit p53. We provide evidence for a contribution of p27 protein induction to the observed p53-independent G1 arrest in response to Hdmx knockdown. In conclusion, our study establishes the importance of Hdmx as an oncogene in a subset of uveal melanomas and widens the spectrum of its function beyond p53 inhibition.

Original languageEnglish
Pages (from-to)492-507
Number of pages16
JournalAmerican Journal of Cancer Research
Volume2
Issue number5
Publication statusPublished - 2012

Cite this

de Lange, J., Teunisse, A. F., Vries, M. V., Lodder, K., Lam, S., Luyten, G. P., ... Jochemsen, A. G. (2012). High levels of Hdmx promote cell growth in a subset of uveal melanomas. American Journal of Cancer Research, 2(5), 492-507.