AURKB Enhances Chromosomal Remodeling of Telomeric Genes and Accelerates Tumorigenesis of Uveal Melanoma

by Selleckchem | Oct 18 2023

Purpose: Uveal melanoma (UM) is the most common intraocular malignancy in adults developing liver metastases, threatening a patient's life. Current therapeutics failed to significantly improve the survival of patients with UM. Thus, the discovery of potent drugs is imminent.

Methods: Integrated bioinformatic analysis of The Cancer Genome Atlas and immunohistochemistry staining of patients' tissues revealed the oncogenic role of aurora kinase B (AURKB) in UM. Drug sensitivity assays and an orthotopic intraocular animal model were used to test the efficacy of AURKB inhibitors. RNA sequencing and immunoblotting were performed to identify the downstream effector. A chromatin immunoprecipitation assay was conducted to elucidate AURKB's transcriptional regulation on the target gene.

Results: AURKB was found overexpressed in patients with UM, resulting in a poor prognosis. Luckily, the AURKB-specific inhibitor, hesperadin, achieved prominent pharmacological efficiency in UM in vitro and in vivo. Mechanically, hesperadin compromised phosphorylation of histone H3 at serine 10 (H3S10ph) at the promoter of telomerase reverse transcriptase, accompanied by methylation of histone H3 at lysine 9. This methylated status of the promoter region forced chromatin condensation and consequently halted the transcription of telomerase reverse transcriptase.

Conclusions: Collectively, our data demonstrated that AURKB inhibitors decelerated UM tumorigenesis by epigenetically silencing the expression of oncogenic telomerase reverse transcriptase, indicating AURKB as a potential therapeutic target in UM.

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Title: AURKB Inhibition as a Potential Therapeutic Strategy for Uveal Melanoma

Abstract: Uveal melanoma (UM) is a common type of intraocular malignancy in adults that frequently develops liver metastases, posing a significant threat to patients' lives. Current treatment options have failed to substantially improve the survival of UM patients, necessitating the discovery of more effective drugs. Through integrated bioinformatic analysis of The Cancer Genome Atlas and immunohistochemistry staining of patients' tissues, we identified the overexpression of aurora kinase B (AURKB) in UM and its association with poor prognosis. We investigated the efficacy of AURKB inhibitors using drug sensitivity assays and an orthotopic intraocular animal model. Our findings revealed that the AURKB-specific inhibitor, hesperadin, exhibited significant pharmacological efficiency in both in vitro and in vivo models of UM. Mechanistically, hesperadin disrupted the phosphorylation of histone H3 at serine 10 (H3S10ph) at the promoter region of telomerase reverse transcriptase (TERT), accompanied by histone H3 lysine 9 methylation. This methylation-induced chromatin condensation resulted in the transcriptional silencing of TERT, a key oncogene in UM. In conclusion, our study demonstrates that AURKB inhibitors can decelerate UM tumorigenesis by epigenetically suppressing the expression of TERT, highlighting AURKB as a potential therapeutic target for UM.

Introduction: Uveal melanoma (UM) is the most prevalent form of intraocular malignancy in adults, and the development of liver metastases severely impacts patient prognosis. Unfortunately, current therapeutic options for UM have shown limited success in significantly improving patient survival. Therefore, the identification of potent drugs that can effectively target UM is crucial. In this study, we investigated the role of aurora kinase B (AURKB) in UM and evaluated the therapeutic potential of AURKB inhibitors.

Methods: To determine the expression and clinical significance of AURKB in UM, we performed integrated bioinformatic analysis using The Cancer Genome Atlas dataset and validated our findings using immunohistochemistry staining of patients' tissue samples. We assessed the efficacy of AURKB inhibitors by conducting drug sensitivity assays and utilizing an orthotopic intraocular animal model of UM. Furthermore, we employed RNA sequencing and immunoblotting techniques to identify downstream effectors of AURKB. To elucidate the transcriptional regulation of the target gene, we conducted chromatin immunoprecipitation assays.

Results: Our analysis revealed the overexpression of AURKB in UM patients, which correlated with a poor prognosis. Encouragingly, treatment with the AURKB-specific inhibitor hesperadin demonstrated significant pharmacological efficacy in both in vitro UM models and an orthotopic intraocular animal model. Mechanistically, hesperadin disrupted the phosphorylation of histone H3 at serine 10 (H3S10ph) at the promoter region of TERT. This alteration was accompanied by methylation of histone H3 at lysine 9, leading to chromatin condensation and subsequent transcriptional silencing of TERT.

Conclusions: Our comprehensive findings provide evidence that AURKB inhibitors can slow down UM tumorigenesis by epigenetically suppressing the expression of the oncogene TERT. This study highlights AURKB as a promising therapeutic target for UM and supports further exploration of AURKB inhibitors as potential drugs for UM treatment.