Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma
Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma
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DOI：
10.1038/s41416-021-01695-1
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发表时间：
2022-01-11
影响因子：
8.8
通讯作者：
Nakashima，Yasuharu
中科院分区：
文献类型：
--
作者：
Shimada，Eijiro;Matsumoto，Yoshihiro;Nakashima，Yasuharu
背景：去分化软骨肉瘤（DDCS）是一种侵袭性骨肿瘤，预后差，目前尚无有效的治疗方法.由于DNA甲基化的变化在DDCS中起关键作用，24我们探索了DNA甲基化在肿瘤发生中的作用，以潜在地确定有效的表观遗传治疗。26方法我们通过计算机模拟分析鉴定了由于DNA甲基化而在DDCS和传统软骨肉瘤（CCS）中下调的基因。在DDCS临床样品中验证了结果，并且在多种软骨肉瘤细胞系（NDCS-1、SW 1353和OUMS-27）中研究了感兴趣基因的分子功能。在体外和体内评价了DNA 30甲基转移酶抑制剂地西他滨的治疗作用。31结果PRKCZ在DDCS中被DNA甲基化特异性下调。过表达32 PRKCZ可抑制NDCS-1和SW 1353细胞的增殖。PRKCZ直接结合并激活ATM，随后是CHK 2的磷酸化和随后的凋亡。34地西他滨通过使PRKCZ的启动子区域去甲基化来增加PRKCZ表达，35这激活ATM/CHK 2途径并通过诱导凋亡来抑制细胞增殖。结论DNA甲基化增加和PRKCZ表达减少通过ATM/CHK 2通路的失活阻止DDCS中的细胞凋亡。地西他滨诱导的PRKCZ 38的表达代表了DDCS的有希望的治疗。39
Background Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with poor 23 prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, 24 we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective 25 epigenetic treatment. 26Methods We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due 27 to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and 28 the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell 29 lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA 30 methyltransferase inhibitor, was evaluated in vitro and in vivo. 31 Results PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of 32 PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and 33 activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. 34 Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, 35 which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. 36 Conclusions Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via 37 inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ 38 represents a promising therapy for DDCS. 39