PUBLICATION
Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor
- Authors
- Sundaramurthi, H., García-Mulero, S., Tonelotto, V., Slater, K., Marcone, S., Piulats, J.M., Watson, R.W., Tobin, D.J., Jensen, L.D., Kennedy, B.N.
- ID
- ZDB-PUB-220216-2
- Date
- 2022
- Source
- Cancers 14(3): (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- ACY-1215, HDAC inhibitor, MITF, ML329, metastatic uveal melanoma, p-ERK, zebrafish xenografts
- MeSH Terms
- none
- PubMed
- 35159049 Full text @ Cancers
Citation
Sundaramurthi, H., García-Mulero, S., Tonelotto, V., Slater, K., Marcone, S., Piulats, J.M., Watson, R.W., Tobin, D.J., Jensen, L.D., Kennedy, B.N. (2022) Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor. Cancers. 14(3):.
Abstract
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 inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. 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 attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h 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, the 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 reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping