Functional assessment of SIRT1 in melanoma progression

Abstract

Malignant melanoma is a type of skin cancer originated from melanocytes that has an increasing incidence and is highly lethal. Both genetic and epigenetic changes have been demonstrated to take part in its development and progression. Epigenetics comprises mechanisms like DNA methylation, histone modifications, chromatin remodeling and mRNA silencing by microRNAs, which are altered in cancer cells. It is known that reactive oxygen species (ROS) can lead to such changes. High levels of ROS can damage DNA, what requires a chromatin rearrangement to be repaired. In this repair process there is the participation of histone acetylases and deacetylases, among which is sirtuin-1 (SIRT1) that, when recruited to damaged sites, leads to transcriptional repression. SIRT1 is a ROS-responsive NAD+-dependent histone deacetylase that is shown to be overexpressed in different cancer cell lineages. The cell lines 4C (pre-cancerous) and 4C11- (non-metastatic melanoma) were obtained from non-tumorigenic melan-a melanocytes put through sequential substrate adhesion impediments cycles, what provides a stressing microenvironment that promotes increased levels of ROS. In these two cell lines, the expression of SIRT1 was increased compared to melan-a melanocytes. Some studies suggest an oncogenic role of SIRT1 in colon and breast cancer and demonstrate that its inhibition leads to reexpression of tumor suppressor genes, what reaffirms the importance of SIRT1 in cancer progression.