The current understanding of how primary tumor cells acquire the capacity to metastasize is still very limited. This becomes a major problem to find effective cures for all types of cancer, as metastatic disease accounts for the majority of cancer-related mortality. Therefore, a deep understanding of the changes that occur in the primary tumor cells that lead them to acquire the ability to escape, migrate, invade, colonize and survive other niches is necessary. Chromatin remodeling is at the intersection of signaling pathways and their ability to elicit cellular changes, such as increased survival, proliferation and metastatic properties. However, the role of chromatin remodeling factors, although studied in primary tumors, remains largely unknown in the metastatic process. Here we propose that chromatin remodeling is mediated by histone chaperones, particularly by suppression of the chromatin assembly factor 1 (CAF-1) complex. Our preliminary data shows that suppression of this complex is sufficient to induce metastatic potential in cells in culture and that CAF-1 suppression is regulated by ERK. We hypothesize that ERK2-mediated CAF-1 suppression leads to a decline in the incorporation of the canonical histone H3.1/H3.2 variants in the chromatin and an increase of H3.3 variant at the promoter of genes that drive the acquisition of metastatic properties. If true, this opens a new line of research in the metastasis field and yields novel potential therapeutic targets to be considered for cancer treatment.
While the majority of primary tumors can be cured by surgery and adjuvant therapy, metastases that arise from these tumors result in greater than 90% of cancer mortality. Tumor cells that acquire metastatic characteristics change dramatically by reprogramming their identity; they become stem-cell-like, resistant to therapies aimed at killing proliferating cells, and are able to spread and survive at distant sites. Thus, by identifying mechanisms that drive the metastatic process we considerably increase the ability to effectively treat cancer.
