Genes expressed in cancer and germline cells group


Etienne De Plaen, Assistant Member

Olga KHOLMANSKIKH, PhD Student

Claudine BLONDIAUX, Technician


E De Plaen

Human tumors express specific antigens arising from the activation of genes, such as MAGE, BAGE, GAGE and LAGE/NY-ESO1, which are normally expressed only in germ cells. As germ cells are not subject to scrutiny by the immune system, antigens encoded by these genes are strictly tumor-specific.

Our group has identified new genes that are specifically expressed in tumors and in germ cells. Most of these genes have their normal site of expression in spermatogonia, the pre-meiotic stage of sperm development, and are located on the X chromosome.

Efforts are now devoted to determining the function of “cancer-germline” genes and deciphering the mechanism leading to their activation in tumor cells.


To analyze the functions of a MAGE protein, MAGE-A1, we searched to identify binding partners of this protein. Using yeast two-hybrid screening, we found interaction between MAGE-A1 and transcriptional regulator SKIP (1). SKIP is an adaptor protein that connects DNA-binding proteins to proteins that activate or repress transcription. Our results suggest that by binding to SKIP and by recruiting histone deacetylase 1, protein MAGE-A1 present in the nucleus represses transcription. In addition, we have observed an interaction between MAGE-A1 and DNA methyltransferases (Dnmt). Since recruitment of Dnmt3a by the Myc transcription factor has been shown to repress the p21Cip1 promoter (2), we are now trying to evaluate whether promoters could be repressed by MAGE-A1 in the presence of Dnmt.

We are also studying the mechanisms leading to the activation of “cancer-germline” genes in tumors. It was previously shown by the group that these genes rely primarily on DNA methylation for their repression in normal somatic tissues, and that their activation in tumors is a consequence of the overall genome demethylation process that often accompanies tumorigenesis. Stable activation of cancer-germline genes in tumors does not require a permanent demethylating activity, but depends on the presence of specific transcription factors that maintain the promoter region unmethylated (3). Antisense-mediated knock-down experiments indicated that DNMT1 is the primary DNA methyltransferase to maintain methylation of cancer-germline genes (4), and that transient down-regulation of this enzyme suffices to induce stable activation of cancer-germline genes. This is supporting the view that hypomethylation of these genes in tumors results from a historical event of demethylation (4).

Finally, in collaboration with Nicolas Van Baren and Francis Brasseur, we are presently analyzing the molecular mechanisms by which IFN-γ inhibits the expression of melanocyte differentiation genes. Preliminary data indicate that this action is mediated by a soluble autocrine factor released by the IFN-γ-treated melanoma cells. We are in the process of isolating and characterizing this factor.

  • Functions of MAGE proteins
    Olga Kholmanskikh and Etienne De Plaen
  • Mechanisms by which IFN-γ inhibits the expression of melanocyte differentiation genes
    Olga Kholmanskikh and Etienne De Plaen (in collaboration with Nicolas Van Baren and Francis Brasseur)

Selected publications


  1. Laduron, S., Deplus, R., Zhou, S., Kholmanskikh, O., Godelaine, D., De Smet, C., Hayward, S.D., Fuks, F., Boon, T. and De Plaen, E. MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription. Nucleic Acids Res 2004;32:4340-4350.
  2. Brenner, C., Deplus, R., Didelot, C., Loriot, A., Vire, E., De Smet, C., Gutierrez, A., Danovi, D., Bernard, D., Boon, T., Pelicci, P.G., Amati, B., Kouzarides, T., de Launoit, Y., Di Croce, L. and Fuks, F. Myc represses transcription through recruitment of DNA methyltransferase corepressor. Embo J 2005;24:336-346.
  3. De Smet, C., Loriot, A. and Boon, T. Promoter-dependent mechanism leading to selective hypomethylation within the 5' region of gene MAGE-A1 in tumor cells. Mol Cell Biol 2004;24:4781-4790.
  4. Loriot, A., De Plaen, E., Boon, T. and De Smet, C. Transient down-regulation of DNMT1 methyltransferase leads to activation and stable hypomethylation of MAGE-A1 in melanoma cells. J Biol Chem 2006;281:10118-10126.

Publications