Dataset Information

Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.

ABSTRACT:

Background

In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS.

Results

First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and KDM6B that were upregulated after cisplatin treatment. Consistent with the clinical data, cisplatin-resistant OS specimens showed lower H3K27me3 levels than sensitive specimens. Then, we evaluated the effects of H3K27me3 alteration on OS chemosensitivity. In vitro inhibition of the histone methyltransferase EZH2 in OS cells decreased H3K27me3 levels and led to cisplatin resistance. Conversely, inhibition of the demethylases KDM6A and KDM6B increased H3K27me3 levels in OS and reversed cisplatin resistance in vitro and in vivo. Mechanistically, with the help of RNA sequencing (RNAseq), we found that PRKCA and MCL1 directly participated in the process by altering H3K27me3 on their gene loci, ultimately inactivating RAF/ERK/MAPK cascades and decreasing phosphorylation of BCL2.

Conclusions

Our study reveals a new epigenetic mechanism of OS resistance and indicates that elevated H3K27me3 levels can sensitize OS to cisplatin, suggesting a promising new strategy for the treatment of OS.

SUBMITTER: He C

PROVIDER: S-EPMC6335728 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.

He Chao C Sun Jian J Liu Chao C Jiang Yuhang Y Hao Yongqiang Y

Clinical epigenetics 20190116 1

<h4>Background</h4>In osteosarcoma (OS), chemotherapy resistance has become one of the greatest issues leading to high mortality among patients. However, the mechanisms of drug resistance remain elusive, limiting therapeutic efficacy. Here, we set out to explore the relationship between dynamic histone changes and the efficacy of cisplatin against OS.<h4>Results</h4>First, we found two histone demethylases associated with histone H3 lysine 27 trimethylation (H3K27me3) demethylation, KDM6A, and K ...[more]

PMID: 30651137

Similar Datasets

Project description:BackgroundOsteosarcoma (OS) is a malignant tumor of the bone mostly observed in children and adolescents. The current treatment approach includes neoadjuvant and adjuvant chemotherapy; however, drug resistance often hinders therapy in OS patients. Also, the post-relapse survival of OS patients is as low as 20%. We therefore planned to understand the molecular cause for its poor prognosis and design an appropriate therapeutic strategy to combat the disease.MethodsWe analyzed OS patient dataset from Gene Expression Omnibus (GEO) and identified the differentially expressed genes and the top deregulated pathways in OS. Subsequently, drugs targeting the major de-regulated pathways were selected and the following assays were conducted- MTT assay to assess cytotoxicity of drugs in OS cells; immunoblotting and immunostaining to analyze key protein expression and localization after drug treatment; LysoTracker staining to monitor lysosomes; Acridine Orange to label acidic vesicles; and DCFDA to measure Reactive Oxygen Species (ROS).ResultsThe differential gene expression analysis from OS patient dataset implicated the striking involvement of cellular processes linked to autophagy and protein processing in the development of OS. We therefore selected the FDA approved drugs, chloroquine (CQ) and verteporfin (VP) known for autophagy inhibitory and proteotoxic functions to explore against OS. Importantly, VP, but not CQ, showed an extensive dose-dependent cytotoxicity. It resulted in autophagy disruption at multiple steps extending from perturbation of early autophagic processes, inhibition of autophagic flux to induction of lysosomal instability. Interestingly, VP treated protein lysates showed a ROS-dependent high molecular weight (HMW) band when probed for P62 and P53 protein. Further, VP triggered accumulation of ubiquitinated proteins as well. Since VP had a pronounced disruptive effect on cellular protein homeostasis, we explored the possibility of simultaneous inhibition of the ubiquitin-proteasomal system (UPS) by MG-132 (MG). Addition of a proteasomal inhibitor significantly aggravated VP induced cytotoxicity. MG co-treatment also led to selective targeting of P53 to the lysosomes.ConclusionHerein, we propose VP and MG induce regulation of autophagy and protein homeostasis which can be exploited as an effective therapeutic strategy against osteosarcoma.

Dataset Information

Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.

Background

Results

Conclusions

Publications

Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets