piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL
piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL
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piRNA-30473 通过调节 DLBCL 中的 m6A RNA 甲基化促进肿瘤发生和不良预后。
DOI：
10.1182/blood.2019003764
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发表时间：
2021-03-25
期刊：
影响因子：
20.3
通讯作者：
Li, Bingzong
中科院分区：
文献类型：
--
作者：
Han, Huiying;Fan, Gao;Li, Bingzong
弥漫性大 B 细胞淋巴瘤 (DLBCL) 的发生和进展受遗传和表观遗传畸变控制。作为最丰富的真核信息RNA修饰，N6-甲基腺苷（m6A）已知可通过调节靶基因影响各种基本生物过程；然而，m6A 修饰在 DLBCL 中的功能尚不清楚。 PIWI 相互作用 RNA (piRNA) 已被证明是癌症中的表观遗传效应子。在这里，我们发现 piRNA-30473 的高表达支持 DLBCL 的侵袭性表型，并且 piRNA-30473 耗竭会降低 DLBCL 细胞的增殖并诱导细胞周期停滞。在异种移植 DLBCL 模型中，piRNA-30473 抑制可减少肿瘤生长。此外，在单变量分析中，piRNA-30473 与总生存期 (OS) 显着相关，并且在多变量分析中调整国家综合癌症网络-国际预后指数 (NCCN-IPI) 后具有统计学意义。其他研究表明，piRNA-30473 通过上调 WTAP（一种 m6A mRNA 甲基化酶）的机制发挥其致癌作用，从而提高整体 m6A 水平。整合转录组和 m6A-seq 分析表明，WTAP 通过增强 HK2 m6A 水平来增加其关键靶基因 HK2 的表达，从而促进 DLBCL 的进展。 piRNA-30473/WTAP/HK2 轴共同通过调节 DLBCL 中的 m6A RNA 甲基化来促进肿瘤发生。此外，通过全面分析我们的临床数据和数据集，我们发现 m6A 调控基因 piRNA-30473 和 WTAP 可以改善 DLBCL 患者的生存预测。我们的研究强调了 m6A 修饰在 DLBCL 中的功能重要性，并可能有助于开发 DLBCL 的预后分层和治疗方法。
The initiation and progression of diffuse large B-cell lymphoma (DLBCL) is governed by genetic and epigenetic aberrations. As the most abundant eukaryotic message RNA modification, N6-methyladenosine (m6A) is known to influence various fundamental bioprocesses by regulating target gene; however, the function of m6A modifications in DLBCL is unclear. PIWI-interacting RNAs (piRNAs) have been indicated to be epigenetic effectors in cancer. Here, we show that high expression of piRNA-30473 supports the aggressive phenotype of DLBCL, and piRNA-30473 depletion decreases proliferation and induces cell cycle arrest in DLBCL cells. In xenograft DLBCL models, piRNA-30473 inhibition reduces tumor growth. Moreover, piRNA-30473 is significantly associated with overall survival (OS) in a univariate analysis, and is statistically significant after adjusting for the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) in the multivariate analysis. Additional studies demonstrate that piRNA-30473 exerts its oncogenic role through a mechanism involving the upregulation of WTAP, an m6A mRNA methylase, thus enhances the global m6A level. Integrating transcriptome and m6A-seq analyses reveal that WTAP increases the expression of its critical target gene HK2 by enhancing the HK2 m6A level, thereby promoting the progression of DLBCL. Together, the piRNA-30473/WTAP/HK2 axis contributes to tumorigenesis by regulating m6A RNA methylation in DLBCL. Furthermore, by comprehensively analyzing our clinical data and datasets, we discover that the m6A regulatory genes piRNA-30473 and WTAP improve survival prediction in DLBCL patients. Our study highlights the functional importance of the m6A modification in DLBCL and might assist in the development of a prognostic stratification and therapeutic approach for DLBCL.