Inhibition of Metastatic Uveal Melanoma Cell Proliferation by the Histone Deacetylase 6 Inhibitor, Ricolinostat, is Linked to Altered Microphthalmia-associated Transcription Factor and Phospho-ERK Expression
Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase 6 inhibitor (HDAC6i), to attenuate MUM cell growth in vitro and in vivo, and elucidate the underlying molecular mechanisms. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo regression of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry analysis revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0006) following 24 hours of treatment and significant apoptosis was triggered in a time- and dose-dependent manner (p = <0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome-profiling, attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329, significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of MUM cells and are potential therapeutic options for MUM.