Epigenetic reprogramming as a key contributor to melanocyte malignant transformation

Author(s):Show less -

Molognoni, Fernanda ; Cruz, Adriana T. ; Meliso, Fabiana M. ; Morais, Alice S. ; Souza, Camila F. ; Xander, Patricia ^[1] ; Bischof, Jared M. ^{[2, 3]} ; Costa, Fabricio F. ^{[2, 3]} ; Soares, Marcelo B. ^{[2, 3]} ; Liang, Gangning ^[4] ; Jones, Peter A. ^[4] ; Jasiulionis, Miriam G. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biol Sci, Sao Paulo - Brazil

^[2] Childrens Mem Res Ctr, Chicago, IL - USA

^[3] Northwestern Univ, Chicago, IL 60611 - USA

^[4] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 - USA

• Document type: Journal article
• Source: Epigenetics; v. 6, n. 4, p. 451-465, APR 2011.
• Web of Science Citations: 21

Abstract

Melanoma progression requires deregulation of gene expression by currently uncharacterized epigenetic mechanisms. A mouse model based on changes in cell microenvironment was developed by our group to study melanocyte malignant transformation. Melanoma cell lines (4C11- and 4C11+) were obtained as result of 5 sequential anchorage blockades of non-tumorigenic melan-a melanocytes. Melan-a cells submitted to 4 de-adhesion cycles were also established (4C), are non-tumorigenic and represent an intermediary phase of tumor progression. The aim of this work was to identify factors contributing to epigenetic modifications in early and later phases of malignant transformation induced by anchorage impediment. Epigenetic alterations occur early in tumorigenesis; 4C cell line shows changes in global and gene-specific DNA methylation and histone marks. Many histone modifications differ between melan-a, 4C, 4C11-(non-metastatic melanoma cell line) and 4C11+ (metastatic melanoma cell line) which could be associated with changes in gene and microRNA expression. These epigenetic alterations seem to play a key role in malignant transformation since melanocytes treated with 5-Aza-2'-deoxycytidine before each anchorage blockade do not transform. Some epigenetic changes seem to be also responsible for the maintenance of malignant phenotype, since melanoma cell lines (4C11- and 4C11+) treated in vitro with 5-Aza-2'-deoxycytidine or Trichostatin A showed reduction of tumor growth in vivo. Changes in gene expression reflecting cell adaptation to new environment were also observed. We propose a model in which sustained microenvironmental stress in melanocytes results in epigenetic reprogramming. Thus, after adaptation, cells may acquire epigenetic marks that could contribute to the establishment of a malignant phenotype. (AU)

• FAPESP's process: 06/61293-1 - DNA methylation contribution to carcinogenesis
• Grantee: Miriam Galvonas Jasiulionis
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 09/03335-8 - Identification of genes that present altered expression due to aberrant promoter methylation in the initial phases of melanoma progression
• Grantee: Alice Santana Morais
• Support type: Scholarships in Brazil - Master