PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Abstract
The MAGE gene family is characterized by a conserved domain
(MAGE Homology Domain). A subset of highly homologous MAGE
genes (group A; MAGE-A) belong to the chromosome X-clustered
cancertestis antigens. MAGE-A genes are normally expressed in
the human germ line and overexpressed in various tumor types;
however, their biological function is largely unknown. Here we
present evidence indicating that MageA2 protein, belonging to the
MAGE-A subfamily, confers wild-type-p53-sensitive resistance to
etoposide (ET) by inducing a novel p53 inhibitory loop involving
recruitment of histone deacetylase 3 (HDAC3) to MageA2p53
complex, thus strongly down-regulating p53 transactivation function.
In fact, enhanced MageA2 protein levels, in addition to ET
resistance, correlate with impaired acetylation of both p53 and
histones surrounding p53-binding sites. Association between
MAGE-A expression levels and resistance to ET treatment is clearly
shown in short-term cell lines obtained from melanoma biopsies
harboring wild-type-p53, whereas cells naturally, or siRNAmediated
expressing low MAGE-A levels, correlate with enhanced
p53-dependent sensitivity to ET. In addition, combined trichostatin
AET treatment in melanoma cells expressing high MAGE-A levels
reestablishes p53 response and reverts the chemoresistance.
