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Abstract
Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review.
Highlights
Uveal melanoma (UM) is the most common primary cancer of the eye, causing fatal liver metastasis in up to half of the patients [1,2]
Short hairpin RNA-mediated depletion of Hdac4 in BRCA1 associated protein 1 (BAP1)-mutant UM cells significantly impeded cell proliferation [37]. These findings suggest novel insights into the role of BAP1 in development and cancer and propose histone deacetylase inhibitors (HDACis) as potential therapeutic agents for BAP1-mutant cancer’s treatment
Epigenetics and epigenomics are new emerging research fields that start to unfold an era of contemporary approaches to improve clinical treatment and decline metastasis risk in UM patients
Summary
Uveal melanoma (UM) is the most common primary cancer of the eye, causing fatal liver metastasis in up to half of the patients [1,2]. Gene expression profiling is considered an important prognostic tool that can predict metastatic risk with higher certainty than clinical stage or chromosome 3 status. DNA damage repair, hypoxia-inducible factor 1 alpha (HIF1A), and MYC signaling are more prominent, while high levels of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt are more noticeable in the other subgroup [15]. This highlights the necessity for tailored therapeutic strategies that target these subtype-specific molecular changes. M3 BAP1-aberrant UM tumors offered a single global DNA methylation profile [15]
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