The Role of N6-Methyladenosine in the Promotion of Hepatoblastoma: A Critical Review

Abstract

Hepatoblastoma (HB) is a rare primary malignancy of the developing fetal liver. Its course is profoundly influenced by genetics, in the context of sporadic mutation or genetic syndromes. Conventionally, subtypes of HB are histologically determined based on the tissue type that is recapitulated by the tumor and the direction of its differentiation. This classification is being reevaluated based on advances on molecular pathology. The therapeutic approach comprises surgical intervention, chemotherapy (in a neoadjuvant or post-operative capacity), and in some cases, liver transplantation. Although diagnostic modalities and treatment options are evolving, some patients experience complications, including relapse, metastatic spread, and suboptimal response to chemotherapy. As yet, there is no consistent framework with which such outcomes can be predicted. N⁶-methyladenosine (m⁶A) is an RNA modification with rampant involvement in the normal processing of cell metabolism and neoplasia. It has been observed to impact the development of a variety of cancers via its governance of gene expression. M⁶A-associated genes appear prominently in HB. Literature data seem to underscore the role of m⁶A in promotion and clinical course of HB. Illuminating the pathogenetic mechanisms that drive HB are promising additions to the understanding of the clinically aggressive tumor behavior, given its potential to predict disease course and response to therapy. Implicated genes may also act as targets to facilitate the evolving personalized cancer therapy. Here, we explore the role of m⁶A and its genetic associates in the promotion of HB, and the impact this may have on the management of this neoplastic disease.

Keywords: N6-Methyladenosine; beta-catenin; hepatoblastoma; hepatoblastoma genetics; m6A; methyltransferase.

Figure 1

The m⁶A methylation is catalyzed by the writer complex, including METTL3, METTL14, METTL16, WTAP. The m⁶A modification is erased by demethylases, including FTO and ALKBH5, where FTO is preferentially responsible for the demethylation of N⁶,2′-O-dimethyladenosine (m⁶A_m) at the 7-methylguanosine cap. The m⁶A-modified RNA reader proteins include YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPC/A2B1. M⁶A modification modulates miRNA biogenesis, inactivation, m⁶A switch, RNA translocation, pre-mRNA splicing, RNA translation, RNA decay, and RNA stability. WTAP, Wilms’ tumor 1-associated protein; eIF3, eukaryotic initiation factor 3; YTHDF, YT521-B homology domain family; YTHDC, YT521-B homology domain-containing protein; IGF2BP, insulin-like growth factor 2 mRNA-binding protein; HNRNP, heterogeneous nuclear ribonucleoproteins; FTO-CTD, FTO C-terminal domain.

Figure 2

METTL16 methylates a stem-loop structure in the 3′ untranslated region (UTR) of S-adenosyl methionine (SAM) synthase, methionine adenosyltransferase 2A (MAT2A). In SAM-repleted conditions, MAT2A is methylated and degraded. Conversely, in SAM-depleted conditions, METTL16 induces splicing and expression of MAT2A.

Figure 3

Methylation of A4220 in 28S ribosomal RNA (rRNA) by zinc finger CCHC domain-containing protein 4 (ZCCHC4) promotes ribosome assembly and translation.

Figure 4

The domain composition of m⁶A enzymes. (Top, writers) m⁶A writers contain methyltransferase (MTase) domains. METTL3 contains Cys-Cys-Cys-His (CCCH) zinc finger motifs. METTL16 has two vertebrate-conserved regions (VCR).