Piwi相互作用RNA
生物
癌变
弥漫性大B细胞淋巴瘤
RNA甲基化
表观遗传学
癌症研究
转录组
核糖核酸
甲基化
癌症
小RNA
DNA甲基化
基因
遗传学
基因表达
RNA干扰
淋巴瘤
甲基转移酶
免疫学
作者
Huiying Han,Fan Gao,Sha Song,Yunxin Jiang,Chenao Qian,Weimin Zhang,Qi Su,Xiaofeng Xue,Wenzhuo Zhuang,Bing-Zong Li
出处
期刊:Blood
[American Society of Hematology]
日期:2020-09-23
卷期号:137 (12): 1603-1614
被引量:147
标识
DOI:10.1182/blood.2019003764
摘要
Abstract The initiation and progression of diffuse large B-cell lymphoma (DLBCL) is governed by genetic and epigenetic aberrations. As the most abundant eukaryotic messenger RNA (mRNA) modification, N6-methyladenosine (m6A) is known to influence various fundamental bioprocesses by regulating the 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 in a univariate analysis and is statistically significant after adjusting for the National Comprehensive Cancer Network-International Prognostic Index 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, and thus enhances the global m6A level. Integrating transcriptome and m6A-sequencing analyses reveals that WTAP increases the expression of its critical target gene, hexokinase 2 (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 data sets, 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.
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