Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro

Neuroblastoma is the most common pediatric solid tumor occurring outside the brain, and it is thought to arise from cells that acquire errors during the normal process of embryonal development. Today, we know that embryonal development is regulated by epigenetics, a mechanism that determines which genes need to be expressed in each cell type and developmental step. Epigenetic errors, therefore, are considered contributory to the appearance and progression of tumors such as neuroblastoma. Here, we aimed at finding whether ZRF1, a known epigenetic regulator, could play a significant role in the aggressiveness of neuroblastoma. Our results suggest that ZRF1 does not seem to have any relevant function in neuroblastoma cells; however, the levels of this epigenetic regulator are related to the prognostic of neuroblastoma patients and could be used to predict their progression and improve the diagnosis. Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma.