Dataset Information

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.

SUBMITTER: Chokhachi Baradaran P

PROVIDER: S-EPMC7432398 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting Epigenetic Modifications in Uveal Melanoma.

Chokhachi Baradaran Pooneh P Kozovska Zuzana Z Furdova Alena A Smolkova Bozena B

International journal of molecular sciences 20200727 15

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, ...[more]

PMID: 32726977

Similar Datasets

Project description:Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic drivers of UM metastasis are loss-of-function mutations in tumor suppressor BAP1, an epigenetic regulator that serves as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, and a key player in global epigenetic regulation. Inactivation of BRCA Associated Protein 1 (BAP1) has been shown to induce widespread epigenetic alterations across multiple model systems. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. Interestingly, we observed significant heterogeneity in the efficacy of different BET inhibitors in UM. While previous clinical trials with two BET inhibitors have failed to show efficacy in UM, our findings highlight substantial differences in the potency of specific BET inhibitors for this malignancy. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and completely prevented detectable metastases in the bones, spinal cord, and brain. Unexpectedly, RNA sequencing revealed a strong transcriptional overlap between BET inhibition and histone deacetylase (HDAC) inhibition-- an approach currently under clinical evaluation for UM treatment. Both BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuronal differentiation-like phenotype in UM cells. Together, our findings demonstrate that UM cells exhibit a distinct vulnerability to BET inhibition and establish BET inhibitors as promising candidates for further clinical evaluation for metastatic UM.

Dataset Information

Targeting Epigenetic Modifications in Uveal Melanoma.

Publications

Targeting Epigenetic Modifications in Uveal Melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets