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

Eijiro Shimada, Yoshihiro Matsumoto, Makoto Nakagawa, Yosuke Susuki, Makoto Endo, Nokitaka Setsu, Toshifumi Fujiwara, Keiichiro Iida, Akira Nabeshima, Kenichiro Yahiro, Atsushi Kimura, Takeshi Hirose, Masaya Kanahori, Ryunosuke Oyama, Yoshinao Oda, Yasuharu Nakashima

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1289-1300
Number of pages12
JournalBritish journal of cancer
Volume126
Issue number9
DOIs
Publication statusPublished - May 18 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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