Genome-wide analysis of DNA methylation identifies the apoptosis-related gene UQCRH in renal cancer
Genome-wide analysis of DNA methylation identifies the apoptosis-related gene UQCRH in renal cancer
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DOI：
10.21203/rs.3.rs-147857/v1
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Kosuke Miyakuni;J. Nishida;D. Koinuma;G. Nagae;H. Aburatani;K. Miyazono;S. Ehata
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文献类型：
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作者：
Kosuke Miyakuni;J. Nishida;D. Koinuma;G. Nagae;H. Aburatani;K. Miyazono;S. Ehata
背景在肾透明细胞癌（ccRCC）中经常观察到DNA高甲基化，并与不良临床结局相关。然而，详细的功能并没有完全揭示。方法在ccRCC细胞中探索DNA甲基转移酶（DNMTs）的靶点。通过在小鼠中连续原位接种建立人ccRCC细胞的高度恶性衍生物。然后，参考RNA测序数据，使用甲基化阵列对DNA甲基化位点进行全基因组分析。结果我们发现DNMT3B上调有助于肾癌的进展，并确定了泛醇细胞色素c还原酶铰链蛋白（UQCRH）作为晚期ccRCC的甲基化靶点。UQCRH在人肾细胞癌组织中的表达低于癌旁正常组织。此外，它的沉默衰减细胞色素c释放响应于凋亡刺激，导致增强的原发性肿瘤形成在体内。此外，DNA去甲基化增强了哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂依维莫司的体内治疗效率。结论DNMT 3B诱导的UQCRH甲基化可能促进肾癌进展，DNMT抑制剂对ccRCC治疗具有潜在的临床意义。
Background DNA hypermethylation is frequently observed in clear cell renal cell carcinoma (ccRCC) and correlates with poor clinical outcomes. However, the detailed function is not fully uncovered. Methods A target for DNA methyltransferases (DNMTs) was explored in ccRCC cells. Highly malignant derivatives of human ccRCC cells were established via serial orthotopic inoculation in mice. Then, DNA methylated sites were genome-widely analyzed using methylation array in reference to RNA-sequencing data. Results We found that DNMT3B upregulation contributes to renal cancer progression and identified the ubiquinol cytochrome c reductase hinge protein (UQCRH) as a methylation target in advanced ccRCC. The expression of UQCRH in human ccRCC tissues was lower than that in normal adjacent tissues. Furthermore, its silencing attenuated cytochrome c release in response to apoptotic stimuli, resulting in enhanced primary tumor formation in vivo. Moreover, DNA demethylation enhanced the therapeutic efficiency of the mammalian target of rapamycin (mTOR) inhibitor everolimus in vivo. Conclusions These findings suggest that the DNMT3B-induced UQCRH methylation may contribute to renal cancer progression and that DNMT inhibitors exhibit potential clinical significance for ccRCC treatment.