Dataset Information

Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

ABSTRACT:

Background

Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment.

Methods

We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo.

Results

PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis.

Conclusions

Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.

SUBMITTER: Shimada E

PROVIDER: S-EPMC9042856 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

Shimada Eijiro E Matsumoto Yoshihiro Y Nakagawa Makoto M Susuki Yosuke Y Endo Makoto M Setsu Nokitaka N Fujiwara Toshifumi T Iida Keiichiro K Nabeshima Akira A Yahiro Kenichiro K Kimura Atsushi A Hirose Takeshi T Kanahori Masaya M Oyama Ryunosuke R Oda Yoshinao Y Nakashima Yasuharu Y

British journal of cancer 20220111 9

<h4>Background</h4>Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment.<h4>Methods</h4>We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DD ...[more]

PMID: 35017658

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Project description:Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2-M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas.SignificanceDDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%-80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.

Dataset Information

Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

Background

Methods

Results

Conclusions

Publications

Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

Similar Datasets

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