Epigenetic Reprogramming by Decitabine in Retinoblastoma.

INTRODUCTION

Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2'-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors.

METHODS

Gene expression analysis of publicly available datasets from patients' primary tumors and normal retina have been compared with those found in WERI-Rb-1 cells to assess the relevance of DAC-driven genes as markers of primary retinoblastoma tumors. The effect of DAC treatment has been evaluated , both in subcutaneous xenografts and in orthotopic models. qPCR analysis of gene expression and Methylation-Specific PCR (MSP) was performed.

RESULTS

Our analysis of network maps for differentially expressed genes in primary tumors compared to DAC-driven genes identified 15 hub/driver genes that may play a pivotal role in the genesis and progression of retinoblastoma. DAC treatment induced significant tumor growth arrest in both subcutaneous and orthotopic xenograft retinoblastoma models. This was associated with changes in gene expression, either through the direct switching-on of epigenetically locked genes or through the indirect regulation of linked genes, suggesting the potential use of DAC as an epigenetic anti-cancer drug for the treatment of retinoblastoma patients.

CONCLUSION

There is a pressing need to develop innovative treatments for retinoblastoma. Our research revealed that DAC can effectively suppress the growth and progression of retinoblastoma in models, offering a potential new therapeutic approach to battle this destructive disease. This discovery highlights the impact of this epigenetic therapy in reprogramming tumor dynamics, and thus its potential to preserve both the vision and lives of affected children.