Cancer cells avoid susceptibility to cell death, often because of mutations in the tumor suppressor protein p53. Such properties make tumor cells particularly dangerous, because they confer not only robust proliferation and invasiveness, but also resistance to standard chemotherapeutic agents. Malignant melanomas show these same characteristics but usually don't have mutations in p53. Soengas et al. report that melanoma cells often have decreased expression of Apaf-1, a protein that acts downstream of p53 in the signaling pathway, leading to cell death. Furthermore, decreased expression of Apaf-1 resulted from epigenetic gene silencing rather than through mutations in the Apaf-1 gene. Agents that suppress DNA methylation or histone deacetylation restored both expression of Apaf-1 and sensitivity to chemotherapeutic agents. Commentary by Jones analyzes the implicated epigenetic control mechanism and emphasizes that the new finding points to possible new therapeutic strategies against this particularly malicious form of cancer.
M. S. Soengas, P. Capoieci, D. Polsky, J. Mora, M. Esteller, X. Opitz-Araya, R. McCombie, J. G. Herman, W. L. Gerald, Y. A. Lazebnik, C. Cordon-Cardo, S. W. Lowe, Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207-211 (2001). [Online Journal]
P. Jones, Cancer: Death and methylation. Nature 409, 141-144 (2001). [Online Journal]