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ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma.

ABSTRACT: Bromodomain-containing protein 4 (BRD4) is overexpressed in thyroid carcinoma, represents as an important therapeutic target. ARV-825 is a novel cereblon-based PROTAC (Proteolysis Targeting Chsimera) compound. It can induce fast and sustained BRD4 protein degradation. Its potential effect in human thyroid carcinoma cells was studied here. In TPC-1 cells and primary human thyroid carcinoma cells, ARV-825 potently inhibited cell viability, proliferation and migration. Furthermore, ARV-825 induced robust apoptosis activation in the thyroid carcinoma cells. ARV-825 induced BRD4 protein degradation and downregulation of its targets, including c-Myc, Bcl-xL and cyclin D1 in thyroid carcinoma cells. It was significantly more potent in inhibiting thyroid carcinoma cells than the known small molecule BRD4 inhibitors. In vivo studies demonstrated that ARV-825 oral administration potently suppressed TPC-1 xenograft tumor growth in severe combined immunodeficient mice. BRD4 protein degradation as well as c-Myc, Bcl-xL and cyclin D1 downregulation were detected in ARV-825-treated TPC-1 tumor tissues. Taken together, ARV-825 induces BRD4 protein degradation and inhibits thyroid carcinoma cell growth in vitro and in vivo.

SUBMITTER: He L

PROVIDER: S-EPMC7093165 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma.

He Ling L Chen Chen C Gao Guoyu G Xu Kun K Ma Zhaoqun Z

Aging 20200312 5

Bromodomain-containing protein 4 (BRD4) is overexpressed in thyroid carcinoma, represents as an important therapeutic target. ARV-825 is a novel cereblon-based PROTAC (Proteolysis Targeting Chsimera) compound. It can induce fast and sustained BRD4 protein degradation. Its potential effect in human thyroid carcinoma cells was studied here. In TPC-1 cells and primary human thyroid carcinoma cells, ARV-825 potently inhibited cell viability, proliferation and migration. Furthermore, ARV-825 induced ...[more]

PMID: 32163373

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Project description:BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL.MethodsExpression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP).ResultsBRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo.ConclusionsBRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

Dataset Information

ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma.

Publications

ARV-825-induced BRD4 protein degradation as a therapy for thyroid carcinoma.

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