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

N6-methyladenosine (m6A), the most abundant modification on eukaryote messenger RNA (mRNA), functions in various fundamental bioprocesses. However, the role of m6A in diffuse large B-cell lymphoma (DLBCL) remains poorly understood. Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, have been documented to be involved in epigenetic regulation of cancer. Here, we reported that piRNA-30473, which expression supported the aggressive phenotype of DLBCL and was correlated with poor prognosis. Moreover, our data indicated that WTAP (m6A mRNA methylase) was downregulated by piRNA-30473 and played a critical oncogenic role in DLBCL. piRNA-30473 or WTAP depletion also reduced proliferation and induced cell cycle arrest, but not apoptosis in DLBCL cells. In “human-in-mouse” xenograft DLBCL models, inhibition of piRNA-30473 led to a significant reduction in tumor volume compared with control. Furthermore, integrating transcriptome and m6A-seq analyses revealed that WTAP through enhancing m6A levels in mRNA transcripts of its critical target gene HK2 and thereby triggering corresponding signaling cascades in DLBCL. Our study highlights the functional importance of m6A modification machinery in DLBCL, and provides profound insights into the molecular mechanism underlying tumorigenesis by revealing a previously unrecognized mechanisms of gene regulation in DLBCL. m6A-seq in SU-DHL-8 cells with or without WTAP knockdown.