Vorinostat Inhibition of FOXM1 Oncogenic Signaling Is Associated With the Downregulation of MYCN Transcription in Metastatic Retinoblastoma

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) class I/II inhibitor that has been evaluated in clinical trials for efficacy in pediatric cancers. Previous studies demonstrated cellular responses to SAHA in retinoblastoma (RB), a pediatric intraocular cancer. However, its mechanism of action remains incompletely understood. In this report, we demonstrate that SAHA inhibition of cell proliferation and induction of cell death was associated with the downregulation of the FOXM1 oncogene in the MYCN-driven RB1-/RB1-cell lines WERI-RB1 and Y79, of which Y79 exhibits greater metastatic potential. SAHA also deregulated cell cycle genes that are targeted by FOXM1. Additionally, SAHA inhibited RB metastatic signaling, including inhibiting the expression of MMP2, a transcriptional target of FOXM1. Further, because SAHA inhibition of FOXM1 positively correlated with suppression of the MYCN oncogene, we demonstrated that genomic knockdown of MYCN in the RB cell lines resulted in FOXM1 downregulation. Finally, we showed that FOXM1 inhibition downregulated NF-κβ and inhibition of FOXM1 suppressed FOXM1 expression in the RB cell lines. Taken together, these results indicated that SAHA inhibition of FOXM1 oncogenic signaling may be mediated by MYCN in RB. Although the current data provide a preclinical rationale for the consideration of SAHA either as a single agent or in combination with other therapies, for the treatment of metastatic RB with MYCN-amplified RB1-/RB1-molecular phenotype, further research is warranted to gain greater insight into FOXM1-MYCN interaction in response to SAHA, in this molecular subtype of RB.