Identifying Transcription Factors That Play an Active Role in Regulating Neuroendocrine Genes in Virus-Positive Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Understanding the molecular mechanisms underlying MCC pathogenesis is crucial for developing effective therapeutic strategies. In this study, we explored the roles of key transcription factors (TFs), namely CHD2, MITF, NFATC2, and PITX2, in regulating neuroendocrine gene expression associated with MCC progression. Using integrative analyses of RNA sequencing data and transcription factor activity profiling, we identified potential regulatory networks involving these TFs and their target genes. Notably, MITF, NFATC2, and PITX2 exhibited substantial transcription factor activity despite lacking differential expression in LT samples compared to GFP, implicating their roles in driving the neuroendocrine transition from fibroblast cells to MCC-like tumor cells. Additionally, despite limitations posed by the IMR90 model system, our findings suggest that CHD2 may play a critical role in MCC development. Furthermore, we discussed potential interactions between these TFs and signaling pathways such as Notch and Wnt, which may contribute to neuroendocrine differentiation and MCC development. Our study highlights the complex interplay between transcriptional regulation and signaling pathways in MCC, emphasizing the importance of these TFs as prospective targets for future research. Further investigations into these regulatory networks may provide valuable insights into MCC biology and towards the development of novel treatment approaches.