FOXD1 Is a Transcription Factor Important for Uveal Melanocyte Development and Associated with High-Risk Uveal Melanoma

Simple Summary Despite successful treatment of primary uveal melanoma (UM), metastases still occur in approximately 50% of the patients. Unfortunately, little is known about the mechanism behind metastasized UM. By reanalyzing publicly available single-cell RNA sequencing data of embryonic zebrafish larvae and validating the results with UM data, we have identified five transcription regulators of interest: ELL2, KDM5B, REXO4, RBFOX2 and FOXD1. The most significant finding is FOXD1, which is nearly exclusively expressed in high-risk UM and is associated with poor survival. FOXD1 is a novel gene which could be involved in the metastatic capability of UM. Elucidating its function and role in metastatic UM could help to understand and develop treatment for UM. Uveal melanoma (UM) is a deadly ocular malignancy, originating from uveal melanocytes. Although much is known regarding prognostication in UM, the exact mechanism of metastasis is mostly unknown. Metastatic tumor cells are known to express a more stem-like RNA profile which is seen often in cell-specific embryonic development to induce tumor progression. Here, we identified novel transcription regulators by reanalyzing publicly available single cell RNA sequencing experiments. We identified five transcription regulators of interest: ELL2, KDM5B, REXO4, RBFOX2 and FOXD1. Our most significant finding is FOXD1, as this gene is nearly exclusively expressed in high-risk UM and its expression is associated with a poor prognosis. Even within the BAP1-mutated UM, the expression of FOXD1 is correlated with poor survival. FOXD1 is a novel factor which could potentially be involved in the metastatic capacity of high-risk UM. Elucidating the function of FOXD1 in UM could provide insight into the malignant transformation of uveal melanocytes, especially in high-risk UM.