PIWIL1 promotes gastric cancer via a piRNA-independent mechanism

Abstract

Targeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, have emerged as promising candidates for targeted cancer therapy. PPD proteins are essential for small noncoding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out the PIWIL1 gene (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that KO significantly changes the transcriptome, causing the up-regulation of most of its associated transcripts. Surprisingly, few bona fide piRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a piRNA-independent function of PIWIL1 in promoting gastric cancer.

Functions of PIWI Proteins in Gene Regulation: New Arrows Added to the piRNA Quiver

“…Although mRNA binding by PIWI proteins without piRNAs has been previously proposed in germ cells [13,18], this PIWI protein mode of action has not been formally demonstrated in germ cells and was not confirmed in subsequent studies [9,11,14]. piRNAs are not present in gastric cancer cells and PIWIL1 was shown to interact with mRNAs independent of piRNAs and repress them through the recruitment of nonsense-mediated mRNA decay components, promoting cancer cell proliferation, migration, and metastasis [67]. How PIWIL1 binds mRNAs without piRNAs remains to be analyzed.…”

Critical Roles of PIWIL1 in Human Tumors: Expression, Functions, Mechanisms, and Potential Clinical Implications

“…Extensive studies have uncovered an important oncogenic role for PIWIL1 in cancer tumor initiation, progression and metastasis (Liu et al, 2006(Liu et al, , 2014Siddiqi et al, 2012;Wang et al, 2012Wang et al, , 2017Zhao et al, 2012;Liang et al, 2013;Wang D.W. et al, 2014;Wang X. et al, 2014;Chen et al, 2015a;Li et al, 2015Li et al, , 2020Xie et al, 2015Xie et al, , 2018Yang et al, 2015;Cao et al, 2016;Araújo et al, 2018;Gao et al, 2018;Jiang et al, 2020;Shi et al, 2020;Zhou et al, 2020; Table 2 and Figure 4). Many studies have demonstrated that PIWIL1 drives tumorigenesis, malignant progression and metastasis by promoting cell migration, invasion, epithelial-mesenchymal transition (EMT), stem-like properties, tumorigenesis and metastasis, while inhibiting apoptosis.…”

“…It will be of great interest to understand whether PIWI proteins could utilize piRNAs as targeting guides to influence the stability of specific mRNA targets in tumor cells (Mai et al, 2018). However, recent observations that PIWIL1 does not associate with piRNAs in pancreatic (Li et al, 2020) and gastric cancer cells (Shi et al, 2020) supported the hypothesis that upregulated PIWIL1 protein probably functions in a piRNA-independent manner in cancer cells.…”

“…Comprehensive functional and mechanistic studies showed that, even in the absence of piRNA loading, PIWIL1 could still promote pancreatic cancer metastasis by acting as a co-activator of the anaphasepromoting complex/cyclosome to degrade a critical cell adhesion-related protein, Pinin (Li et al, 2020). Furthermore, a piRNA-independent mechanism has been proposed to account for the oncogenic functions of PIWIL1 in gastric cancer cells (Shi et al, 2020). Their results suggested that PIWIL1 can significantly boost cell proliferation, migration, tumorigenesis and metastasis by forming a complex with UPF1, UPF2, SMG1 and other components to degrade mRNAs and lncRNAs with tumor suppressor potential (Shi et al, 2020).…”

“…Growing evidence showed that PIWIL1 tends to exhibit tumor-promoting roles in sustaining tumor cell proliferation and activating invasion and metastasis (Suzuki et al, 2012;Tan et al, 2015). Although the molecular basis underlying the oncogenic functions of PIWIL1 remains largely unknown, PIWIL1 has been recently found to regulate the occurrence and progression of human cancers possibly through piRNA-independent mechanisms (Genzor et al, 2019;Li et al, 2020;Shi et al, 2020). Given that the expression of PIWIL1 is mostly restricted to the testis (Qiao et al, 2002) and broadly elevated in various tumors, PIWIL1 has the potential to be ideal targets for cancer diagnosis and therapy.…”