Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target

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. 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 and 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 in 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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Conjunctival Melanoma: Genetic and Epigenetic Insights of a Distinct Type of Melanoma

“…In the eye, EZH2 protein expression can be detected in the keratinocytes of normal conjunctiva, but it has not been found in normal conjunctival melanocytes and PAM. EZH2 is highly expressed in 50% of primary conjunctival melanomas and 88% of lymph node metastases [46]. High EZH2 is correlated with CjM thickness and poor prognosis.…”

“…Inactivation of EZH2 upregulates the oncogene p21/CDKN1A , that controls cellular transition from the G1 to S phase. Moreover, p21 levels are higher after the genetic than the pharmacological inhibition of EZH2, suggesting that EZH2 can regulate transcription using different pathways in addition to its catalytic activity [46]. Inhibition of EZH2 in CjM cells slows the cellular progression to the S-phase and determines cell death through apoptosis and autophagy.…”

“…Furthermore, an increased telomerase activity with TERT promoter mutations can be found in about 40% of conjunctival melanomas [41,42]. In addition, molecular features of this tumor may also include the overexpression of HSP90 and Bcl-2, the inactivation of p16, other minor chromosome abnormalities and miRNAs upregulation [43,44,45,46]. However, none of these genetic or epigenetic alterations seems to have a prognostic role in CjM.…”

EZH2 dysregulation: Potential biomarkers predicting prognosis and guiding treatment choice in acute myeloid leukaemia

“…7 Evidence showed that EZH2 may have a dual role in cancer development, acting as a tumour suppressor or an oncogene depending on the type of cancer. [9][10][11] However, EZH2 inactivation medicated by mutation or under-expression in myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) can contribute to disease pathogenesis and is associated with a poor prognosis. [9][10][11] However, EZH2 inactivation medicated by mutation or under-expression in myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) can contribute to disease pathogenesis and is associated with a poor prognosis.…”

“…8 Overexpression of EZH2 was observed in numerous solid tumours, and targeting EZH2 can cause regression of carcinogenesis. [9][10][11] However, EZH2 inactivation medicated by mutation or under-expression in myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) can contribute to disease pathogenesis and is associated with a poor prognosis. [12][13][14][15] In AML, EZH2 mutation was associated with −7/del(7q) and low bone marrow blast percentage but not affected prognosis.…”