Targeting Epigenetic Modifications in Uveal Melanoma

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.

KIT Expression Is Regulated by DNA Methylation in Uveal Melanoma Tumors

“…Furthermore, DNA methylation or histone modifications can be restored using nuclease-deficient Cas9 (dCas9) protein fused or noncovalently bound to epigenetic effectors. Epigenetic editing by CRISPR/dCas9 allows for locus-specific control of epigenetically regulated gene expression and provides a more specific alternative to epigenetic drugs [ 53 ]. Epigenetic therapy has taken a long time to be accepted for the treatment of solid tumors.…”

The essential role of N6-methyladenosine RNA methylation in complex eye diseases

“… 130 , 131 In people with UM, nine genetic mutations have been identified: GNAQ, GNA11, BAP1, SF3B1, EIF1AX, CYSLTR2, SRSF2, MAPKAPK5 , and PLCB4 . 132 , 133 Abnormal epigenetic factors, 134 , 135 such as DNA methylation, are generally considered to be the major epigenetic factors mediating the development of UM. RASSF1A and p16INK4a are the key genes for hypermethylation and, thus lose their inhibitory effect on UM development.…”

Integrating single-cell analysis and machine learning to create glycosylation-based gene signature for prognostic prediction of uveal melanoma

“…Moreover, glycosylation has the potential to act as a prognostic indicator, as a signature of glycosylation-related genes (GRGs) was shown to predict clinical outcomes in ovarian cancer patients ( 15 ). Other post-translational regulatory mechanisms, such as ubiquitination ( 16 ), phosphorylation ( 17 ) and epigenetic modifications ( 18 ) have also been reported as potential biomarkers in UM prognostic models. However, despite being one of the most crucial post-transcriptional alterations among the 300 protein modifications, few studies have explored the relationship between GRGs signature and the tumor microenvironment (TME) of UM.…”