The impact of the RASSF1C and PIWIL1 on DNA methylation: the identification of GMIP as a tumor suppressor.
The impact of the RASSF1C and PIWIL1 on DNA methylation: the identification of GMIP as a tumor suppressor.
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DOI：
10.18632/oncotarget.27795
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发表时间：
2020-11-10
期刊：
影响因子：
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通讯作者：
Reeves ME
中科院分区：
文献类型：
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作者：
Amaar YG;Reeves ME
前言：最近我们发现了一个新的促进肺癌细胞生长和迁移的RASSF1C-PIWIL1-piRNA途径。Piwi类蛋白与piRNAs相互作用形成复合体，在转录和翻译水平上调节基因的表达。我们在以前的工作中已经说明了RASSF1C调控PIWIL1-piRNA基因轴的表达，这表明RASSF1C-PIWI-piRNA途径可能在一定程度上通过调节癌基因和肿瘤抑制基因的基因甲基化而促进肺癌干细胞的发育和进展。因此，我们使用非小细胞肺癌(NSCLC)细胞模型来验证这一假设，以确定受RASSF1C-PIWIL1-PiRNA途径调控的候选差异甲基化区域(DMRS)。材料和方法：采用亚硫酸盐还原测序法(RRBS)研究RASSF1C过表达、RASSF1C和PIWIL1表达下调对非小细胞肺癌细胞株H1299全基因DNA甲基化的影响。结果：通过比较实验细胞和对照细胞的DNA甲基化图谱，鉴定出DMR。RASSF1C的过表达和RASSF1C和PIWIL1的下调调控了基因组区域的DNA甲基化；在肺癌细胞中发现了位于DMR区域的有统计学意义的候选基因，包括癌基因和肿瘤抑制基因。其中一个高甲基化基因，Gem相互作用蛋白(GMIP)，显示出肿瘤抑制特性。GMIP的表达抑制了肺癌细胞的迁移，其过度表达与肺癌患者较长的生存期有关。结论：RASSF1C-PIWI-piRNA通路调控关键癌基因和抑癌基因。GMIP通过这一途径高度甲基化，具有肿瘤抑制作用。
Introduction: Recently we have identified a novel RASSF1C-PIWIL1-piRNA pathway that promotes lung cancer cell progression and migration. PIWI-like proteins interact with piRNAs to form complexes that regulate gene expression at the transcriptional and translational levels. We have illustrated in previous work that RASSF1C modulates the expression of the PIWIL1-piRNA gene axis, suggesting the hypothesis that the RASSF1C-PIWI-piRNA pathway could potentially contribute to lung cancer stem cell development and progression, in part, through modulation of gene methylation of both oncogenic and tumor suppressor genes. Therefore, we tested this hypothesis using a non-small cell lung cancer (NSCLC) cell model to identify Candidate Differentially Methylated Regions (DMRs) modulated by the RASSF1C-PIWIL1-piRNA pathway. Materials and Methods: We studied the impact of over-expressing RASSF1C and knocking down RASSF1C and PIWIL1 expression on global gene DNA methylation in the NSCLC cell line H1299 using the Reduced Representation Bisulfite Sequencing (RRBS) method. Results: DMRs were identified by comparing DNA methylation profiles of experimental and control cells. Over-expression of RASSF1C and knocking down RASSF1C and PIWIL1 modulated DNA methylation of genomic regions; and statistically significant candidate genes residing DMR regions in lung cancer cells were identified, including oncogenes and tumor suppressors. One of the hypermethylated genes, Gem Interacting Protein (GMIP), displays tumor suppressor properties. GMIP expression attenuates lung cancer cell migration, and its over-expression is associated with longer survival of lung cancer patients. Conclusions: The RASSF1C-PIWI-piRNA pathway modulates key oncogenes and tumor suppressor genes. GMIP is hypermethylated by this pathway and has tumor suppressor properties.