Inhibiting the Inhibitor: MDM4 as a Therapeutic Target in Cutaneous Melanoma

TP53 is well-established as a tumor suppressor gene, but it is rarely mutated in melanoma. Instead, the p53 tumor-suppressor pathway is functionally inactivated in melanoma by other mechanisms, such as upregulation of MDM2 and MDM4 or inactivation of ARF. Strategies for restoring TP53 activity hold promise for therapy of melanoma (JW Dermatol Mar 23, 2012).

Gembarska and colleagues found that MDM4 was upregulated in 65% of melanomas, irrespective of BRAF or NRAS status. Overexpression of Mdm4 in mouse melanocytes cooperated with mutant NRAS to accelerate the formation of aggressive melanomas. Conversely, reduction of MDM4 levels resulted in the arrest and TP53-dependent apoptosis of melanoma cell lines, even those resistant to BRAF inhibitor…