PUBLICATION
Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target
- Authors
- Cao, J., Pontes, K.C.S., Heijkants, R.C., Brouwer, N.J., Groenewoud, A., Jordanova, E.S., Marinkovic, M., van Duinen, S., Teunisse, A.F.A.S., Verdijk, R.M., Snaar-Jagalska, E., Jochemsen, A.G., Jager, M.J.
- ID
- ZDB-PUB-180509-13
- Date
- 2018
- Source
- The Journal of pathology 245(4): 433-444 (Journal)
- Registered Authors
- Snaar-Jagalska, Ewa B.
- Keywords
- EZH2, cell death, conjunctival melanoma, histone methylation, primary acquired melanosis, zebrafish
- MeSH Terms
-
- Up-Regulation
- Humans
- Gene Expression Regulation, Neoplastic
- Antineoplastic Agents/pharmacology*
- Cell Line
- Xenograft Model Antitumor Assays
- RNA Interference
- Cell Cycle Checkpoints/drug effects
- Aged
- Animals
- Pyridones/pharmacology*
- Molecular Targeted Therapy
- Middle Aged
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Adult
- Young Adult
- Melanoma/drug therapy*
- Melanoma/genetics
- Melanoma/metabolism
- Melanoma/secondary
- Tumor Burden/drug effects
- Signal Transduction/drug effects
- Cell Proliferation/drug effects
- Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors*
- Enhancer of Zeste Homolog 2 Protein/genetics
- Enhancer of Zeste Homolog 2 Protein/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Conjunctival Neoplasms/drug therapy*
- Conjunctival Neoplasms/genetics
- Conjunctival Neoplasms/metabolism
- Conjunctival Neoplasms/pathology
- Female
- Zebrafish
- Aged, 80 and over
- Male
- PubMed
- 29732557 Full text @ J. Pathol.
Citation
Cao, J., Pontes, K.C.S., Heijkants, R.C., Brouwer, N.J., Groenewoud, A., Jordanova, E.S., Marinkovic, M., van Duinen, S., Teunisse, A.F.A.S., Verdijk, R.M., Snaar-Jagalska, E., Jochemsen, A.G., Jager, M.J. (2018) Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target. The Journal of pathology. 245(4):433-444.
Abstract
Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier Enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy. Immunohistochemical analysis showed that EZH2 protein expression was absent in normal conjunctival melanocytes and primary acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and seven (88%) of eight lymph node metastases. An increased expression was positively associated with tumour thickness (p=0.03). Next, we targeted EZH2 with specific inhibitors (GSK503 and UNC1999) or depleted EZH2 by stable shRNA knockdown in three primary CM cell lines. Both pharmacological as well as genetic inactivation of EZH2 inhibited cell growth and colony formation and influenced EZH2-mediated gene transcription and cell cycle profile in vitro. The tumour suppressor gene p21/CDKN1A was especially upregulated in CM cells after EZH2 knockdown CM cells. Additionally, the potency of GSK503 against CM cells was monitored in zebrafish xenografts. GSK503 profoundly attenuated tumour growth in CM xenografts at a well-tolerated concentration. Our results indicate that elevated levels of EZH2 are relevant to CM tumourigenesis and progression, and that EZH2 may become a potential therapeutic target for patients with CM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping