piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL

• Published in: Blood 2021-03, Vol.137 (12), p.1603-1614
• Main Authors: Han, Huiying, Fan, Gao, Song, Sha, Jiang, Yunxin, Qian, Chen'ao, Zhang, Weimin, Su, Qi, Xue, Xiaofeng, Zhuang, Wenzhuo, Li, Bingzong
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019003764

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. •piRNA-30473 promotes DLBCL progression by regulating m6A RNA methylation in DLBCL.•piRNA-30473 improves the prognostic stratification and National Comprehensive Cancer Network-International Prognostic Index score of DLBCL. [Display omitted]