Role of m6A methyltransferase component VIRMA in multiple human cancers (Review)

It was first reported that VIRMA is required for the entire process of mRNA methylation in human cells in 2015 [18]. As a VIRMA homologue in Drosophila melanogaster, virilizer plays an essential role in sex-lethal splicing, male and female viability, and the capability of eggs production in embryonic development [33]. In human, VIRMA is located in the nuclear speckles, the same location as that of WTAP [34, 35]. As the largest known component of the methyltransferase complex (202 kDa), VIRMA contains an N-terminal (1130 aa) as N-VIRMA and a C-terminal (1131–1812 aa) as C-VIRMA, and begins from a SUN domain (130 aa) (Fig. 2) [22, 36, 37]. A fourfold decrease in m6A peak scores has been reported following VIRMA knockdown, more obvious than that observed in human cells following METTL3 and METTL14 knockdown [18]. It was reported that in human HeLa cells, VIRMA could recruit the m6A methyltransferase components METTL3/METTL14/WTAP to guide region-selective methylations [38], suggesting that VIRMA plays a significant role in m6A modification. The m6A modification by VIRMA is enriched in the 3′-untranslated region (3′-UTR) and near the stop codon of RNA substrates [20, 38]. Virilizer contains an RNA-binding protein (RBP) domain, similar with that in RNA and DNA helicases, and ribonucleoproteins, and is involved in the RNA processes of metabolism, transport and translation [33]. Studies have demonstrated that the abnormal expression of RBPs could lead to the upregulation of certain oncogenes or the downregulation of certain tumor suppressor genes [39]. VIRMA has been reported to mainly act as the oncogene in several types of cancer, as listed in Table 1. Wang et al. [40] found that hsa_circ_0084922 (also named circ_KIAA1429), coming from VIRMA, was upregulated in hepatocellular carcinoma (HCC), which may promote cancer progression.

m6A regulators, including ‘writers’, ‘erasers’, ‘readers’, play key roles in cancer. VIRMA was found to be correlated with the most positive oncogenic pathways among the ‘writers’ [41], indicating that VIRMA may has multiple different functions and plays important roles in cancer pathways.

As shown in Fig. 4, several m6A modification regulators participate in cancer development in an m6A-dependent manner by targeting related mRNAs. As regards the regulatory role of VIRMA in cancer, it was found that, in addition to the m6A-dependent pathway, VIRMA could also regulate downstream m6A-independent pathways. Circ_KIAA1429 could also regulate downstream m6A-dependent pathways. The expression of VIRMA may also be regulated by miR-143-3p in cancer cells.

While the roles of m6A modifications in cancers have been extensively reviewed elsewhere, the crucial functions of VIRMA in various types of cancer, as well as the potential targeting of VIRMA as cancer treatment, have not yet been highlighted. Our review is to summarize and analyze the present research on VIRMA, provide more ideas for the future research.

More studies are needed to demonstrate the biological function of VIRMA and its impact on tumor progression and survival, as well as the mechanisms involved, in more cancer types and phenotypes. High expression of VIRMA has been verified to predict poor survival in multiple cancers, such as breast cancer [20, 41, 42], liver cancer [29, 43], kidney cancer [44] and prostate cancer [58]. The expression of VIRMA is up-regulated in KIRC, but it indicates a poor prognosis. The study did not explain the reason for this conflict, which need further exploration [41]. VIRMA not only regulates the expression of downstream mRNA, but also regulates the stability of pre-mRNAs and lncRNAs. Inhibiting these downstream targets could reverse the oncogenic effect of VIRMA in cancer progression. Generally, VIRMA is an oncogene in most types of cancer, and downregulating it could inhibit cancer progression, indicating that VIRMA can become a diagnostic/prognostic biomarker in certain cancer types. Based on the emerging evidence of the roles and the molecular mechanisms in cancers, m6A regulators have attracted growing investigation as therapeutic targets [72]. Given the critical roles of the m6A regulatory proteins in cancers, m6A modification ‘eraser’ FTO appears to be a good drug target in cancer therapy. Several FTO small-molecule inhibitors, including meclofenamic acid [73] and MO-I-500 [74] have shown effective activity to inhibit the survival and growth of GBM and breast cancer cells by inhibiting the catalytic activity of FTO. Thus, inhibiting VIRMA and these downstream targets are considered potent cancer therapies. Studies have not yet elucidated the mechanism underlying the downstream regulation of VIRMA and whether it occurs through the m6A pathway in several tumor models, which is crucial for the development of treatments. The underlying mechanisms of VIRMA in cancer should be further addressed. Novel therapeutic strategies for m6A RNA methylation should be further explored in the treatment of cancer.