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Verification of EZH2 as a druggable target in metastatic uveal melanoma.

ABSTRACT: BACKGROUND:Hepatic metastasis develops in ~?50% of uveal melanoma (UM) patients with no effective treatments. Although GNAQ/GNA11 mutations are believed to confer pathogenesis of UM, the underlying mechanism of liver metastasis remains poorly understood. Given that profound epigenetic evolution may occur in the long journey of circulating tumor cells (CTCs) to distant organs, we hypothesized that EZH2 endowed tumor cells with enhanced malignant features (e.g., stemness and motility) during hepatic metastasis in UM. We aimed to test this hypothesis and explore whether EZH2 was a therapeutic target for hepatic metastatic UM patients. METHODS:Expression of EZH2 in UM was detected by qRT-PCR, Western blotting and immunohistochemistry staining. Proliferation, apoptosis, cancer stem-like cells (CSCs) properties, migration and invasion were evaluated under circumstances of treatment with either EZH2 shRNA or EZH2 inhibitor GSK126. Antitumor activity and frequency of CSCs were determined by xenografted and PDX models with NOD/SCID mice. Hepatic metastasis was evaluated with NOG mice. RESULTS:We found that EZH2 overexpressed in UM promoted the growth of UM; EZH2 increased the percentage and self-renewal of CSCs by miR-29c-DVL2-?-catenin signaling; EZH2 facilitates migration and invasion of UM cells via RhoGDI?-Rac1 axis. Targeting EZH2 either by genetics or small molecule inhibitor GSK126 decreased CSCs and motility and abrogated the liver metastasis of UM. CONCLUSIONS:These findings validate EZH2 as a druggable target in metastatic UM patients, and may shed light on the understanding and interfering the complicated metastatic process.

SUBMITTER: Jin B

PROVIDER: S-EPMC7055080 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Verification of EZH2 as a druggable target in metastatic uveal melanoma.

Jin Bei B Zhang Ping P Zou Hailin H Ye Huijing H Wang Yun Y Zhang Jing J Yang Huasheng H Pan Jingxuan J

Molecular cancer 20200304 1

<h4>Background</h4>Hepatic metastasis develops in ~ 50% of uveal melanoma (UM) patients with no effective treatments. Although GNAQ/GNA11 mutations are believed to confer pathogenesis of UM, the underlying mechanism of liver metastasis remains poorly understood. Given that profound epigenetic evolution may occur in the long journey of circulating tumor cells (CTCs) to distant organs, we hypothesized that EZH2 endowed tumor cells with enhanced malignant features (e.g., stemness and motility) duri ...[more]

PMID: 32127003

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Project description:Importance:Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy. Objective:To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM. Design, Setting, and Participants:An experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between 64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining. Main Outcomes and Measures:Interferon ? production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM. Results:Of the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P?=?.005), ciliary body involvement (59% vs 26%; P?=?.008), and amplification of chromosome 8q (66% vs 23%; P?=?.002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNA in 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I. Conclusions and Relevance:PRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.

Dataset Information

Verification of EZH2 as a druggable target in metastatic uveal melanoma.

Publications

Verification of EZH2 as a druggable target in metastatic uveal melanoma.

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