Tumorigenesis is a complex biological process, closely related to the activation of oncogenes and the inactivation of tumor suppressor genes (Jemal et al., 2011). Chromatin modification and transcriptional regulation are crucial biological processes. Increasing number of conserved protein domains, including the YEATS domain, are involved in this process. As a member of a relatively newly discovered epigenetic reading protein family, characterized by the presence of N-terminal YEATS domain (Schulze et al., 2009), YEATS4 was first identified and isolated from glioblastoma in 1997 (Fischer et al., 1997); therefore, it is also known as the glioma amplification gene (GAS41). YEATS4 is a highly conserved nuclear protein gene, and the protein encoded by it is an important chromatin-remodeling molecule, that is, involved in epigenetic regulation. Further research has found that YEATS4 is amplified and overexpressed in various types of malignancies [such as astrocytomas, uterine fibroids, liposarcoma, breast cancer, liver cancer, pancreatic cancer, gastric cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, and other cancers (Fischer et al., 1996; Fischer et al., 1997; Debernardi et al., 2002; Barretina et al., 2010; Park et al., 2011; Schmitt et al., 2012; Pikor et al., 2013; Kim et al., 2015; Kiuchi et al., 2018; Berta et al., 2021)], resulting in malignant progression and poor prognosis of tumors.

Previous studies have revealed that YEATS4 is mainly involved in chromatin modification and transcriptional regulation (Doyon et al., 2004; Cai et al., 2005) by interacting with its target genes, MYC, KIAA1009, AF10, TACC1, NuMA, MYCN, TFIIF, PFDN1, TACC2, and AP-2 beta (Harborth et al., 2000; Debernardi et al., 2002; Lauffart et al., 2002; Ding et al., 2006; Heisel et al., 2010). In addition, YEATS4 plays an important role in the regulation of DNA repair during replication. The upregulation of YEATS4 promotes DNA damage repair and prevents cell death, whereas its downregulation inhibits DNA replication and induces apoptosis. Therefore, the development of small-molecule inhibitors targeting YEATS4 has become an attractive challenge, which can be achieved by reducing or inhibiting the expression of YEATS4 or preventing interactions between YEATS4 and other molecules. However, most current research on YEATS4 focuses on promoting cell growth and viability, while relatively few studies have been conducted on the development of small-molecule inhibitors. Notably, the biological function, precise underlying mechanism, and prognosis of YEATS4 have not yet been fully elucidated. Therefore, an intensive study needs to be conducted on YEATS4.

This review aims to provide a comprehensive overview of the function and carcinogenic effects of YEATS4 and facilitate further exploration of therapeutic targets and prognostic biomarkers for various cancers.

YEATS4 gene contains 103084 bases and is localized in the nucleus. It is localized on human chromosome 12q13-15, and its encoded protein consists of 227 amino acids with a molecular weight of approximately 26.7kD (Wang et al., 2018). There are four types of human YEATS domain proteins: eleven-nineteen-leukemia (ENL), ALL1-fused gene from chromosome 9 protein (AF9), YEATS2, and YEATS domain-containing protein 4 (YEATS4). The N-terminus of YEATS4 contains a highly conserved YEATS domain, a common component of the YEATS domain protein family (Harborth et al., 2000). The C-terminus is a negatively charged α-helix structure, an area of interaction between proteins, that is, species-specific (Piccinni et al., 2011). Evolutionarily, YEATS4 is highly conserved (Zimmermann et al., 2002), and as a member of the YEATS protein family, YEATS4 has high homology with AF9 and ENL. However, it also has some unique structures and functions.

YEATS4 is a structurally incomplete transcription factor that does not contain a DNA-binding domain bound to other gene promoter regions, so it cannot bind to DNA. However, it contains a DNA-activating domain that binds to and activates other transcription factors and promotes their binding to DNA, promoting the expression of target genes (Heisel et al., 2010). Yaf9 is a yeast YEATS domain protein with 80% similarity and 53% identity to YEATS4, and most similarities are found in the N-terminal region (Schulze et al., 2010). This suggests that there may also be heightened functional similarities between Yaf9 and YEATS4, which proved to be the case. In Saccharomyces cerevisiae, Yaf9 constitutes the histone acetyltransferase complex NuA4 and the chromatin remodeling complex SWR1 (Le Masson et al., 2003; Bianchi et al., 2004). In mammals, YEATS4 is a subunit of the SRCAP and Tip60 complexes, which correspond to NuA4 and SWR1 complexes in yeast. The involvement of Yaf9 and YEATS4 as part of a complex that can alter chromatin structure and promote gene transcription suggests that Yaf9 and YEATS4 can facilitate the localization of these complexes to the promoter regions of target genes in yeast and mammals (Zhang et al., 2004). These studies indicate that yeast may be a good choice to use as a model to study the structure, function, and mechanism of YEATS4 in mammalian cells.

Like other YEATS proteins, YEATS4 functions to reconstruct chromosome conformation and regulate transcription, and is involved in the composition of SRCAP and TIP60/TRRAP chromatin remodeling complexes (Cai et al., 2005). Spindle formation-related proteins, such as NuMA, human transformed acid coil 1 protein (TACC1),-tubulin, interact with YEATS4, which is complex and important for spindle formation. NuMA-YEATS4 imbalance may produce abnormal spindles and chromatin, which play a critical role in cell proliferation and cycle formation (Yeewa et al., 2022).

YEATS4 is an epigenetic reader capable of recognizing acetylated lysine residues. First, YEATS4 can bind histone H3 near the promoter of the target gene through its YEATS domain, and is specific for the binding of histones H3K27ac and H3K14ac, thereby promoting the deposition of the histone variant H2A.Z and transcriptional activation of the target gene (Figure 1A) (Hsu et al., 2018). The two YEATS4 molecules can also form dimers through their α-helix structure at the C-terminus, which can bind to diacetylated H3 with higher affinity and preferentially bind to H3K18ac and H3K27ac, demonstrating a unique binding pattern of acetylated histones (Figure 1B) (Cho et al., 2018). At a lower pH, YEATS4 can also bind to succinylated lysine (Ksuc), and YEATS4 can cooperate with H3K122suc and show strong affinity (Figure 1C) (Wang et al., 2018). In addition, HDAC3 mediates transcriptional inhibition through YEATS4 and the co-inhibitor DMAP1, thereby affecting H2A acetylation and transcriptional regulation (Figure 1D) (Witt et al., 2009; Ukey et al., 2022).

lncAKHE is a long-stranded non-coding RNA (lncRNA) that binds to YEATS4 and drives enhanced recognition of the NOTCH2 promoter region by RNA Pol II, thereby promoting the transcription and translation of the NOTCH2 gene and activation of the NOTCH2 signaling pathway (Figure 1E) (Huang et al., 2018). It has also been shown that the recognition of H3K27ac by YEATS4 can promote the transcriptional expression of Lmo4 and recruit the Dot1l-RNA Pol II complex to the promoter of the Lmo4 gene, which is necessary for α4β7+CLP differentiation to ILC (Figure 1F) (Liu et al., 2019). As a member of the zinc finger protein family, ZEB1 induces epithelial-mesenchymal (EMT) transformation of tumor cells (Zhang et al., 2015). YEATS4 promotes ZEB1 expression by interacting with histone H3K27ac in the promoter region of the ZEB1 oncogene (Figure 1G) (Li et al., 2021). MLL translocates with AF10 to produce a fusion protein, MLL/AF10, in which the leucine motif of AF10 is preserved. INI1 (integrase interactor 1) is part of the important chromatin remodeling complex SWI/SNF and can interact with YEATS4 via AF10 interaction, suggesting that these three proteins may exist in the same chromatin complex and work together to influence normal gene regulatory functions (Figure 1H) (Debernardi et al., 2002).

YEATS4 plays a role in the development and progression of many cancers, and its expression is involved in tumor cell proliferation, invasion, metastasis, epithelial-mesenchymal transition transformation, and treatment resistance. Previous studies have shown that, as a transcriptional activator, YEATS4 is mainly involved in P53 pathway, NOTCH pathway, and-catenin pathways.

Numerous studies have shown that YEATS4 is amplified during cancer progression (Vogelstein et al., 2013). In contrast, the knockdown of YEATS4 was followed by the suppression of all typical features of tumor cells, suggesting that YEATS4 may be a potential therapeutic target and a prognostic biomarker for cancer. However, according to the available experimental results, the molecular mechanisms of YEATS4 in different types of tumor cells are not the same (Table 1).

As a newly emerging oncogene, YEATS4 plays a vital role in promoting the occurrence of various tumors. The molecular mechanisms of YEATS4 in various cancers are also different, and similarities in molecular mechanisms or interactions in other cancers require further validation. Despite chemotherapy, radiotherapy, and comprehensive treatment, cancer remains the leading cause of death worldwide, and many cancers are difficult to detect early and have a poor prognosis. If we can intervene at the level of genes related to the onset and progression of tumors, it will open up new avenues for the treatment of tumors.

Based on the molecular mechanism of YEATS4’s role in cancer, the development of drugs targeting YEATS4 to inhibit its activity and function may exert an effect on cancer treatment. This can be done primarily by screening for compounds capable of acetylation with histone lysine at specific sites, thereby neutralizing the transcriptional activation of target genes (Londregan et al., 2022). The channel-like structure formed by the acetolysine-binding site of the YEATS domain, although partially exposed to solvents, does not form deep pockets, which presents a significant obstacle to the development of small-molecule conjugates for YEATS4 (Linhares et al., 2020). Dymytrii et al. designed a dimer inhibitor based on fragment screening to bind to dimerized YEATS4, block the acetyl-lysine binding channel of the YEATS domain, and impair the recognition and binding of acetylated histone H3 by YEATS4, thereby inhibiting the proliferation of non-small cell lung cancer cells (Listunov et al., 2021). However, the low activity of such inhibitors is not sufficient to achieve a potency comparable to that of bromodomain inhibitors, indicating a significant challenge in developing molecular drugs targeting YEATS4.

Nevertheless, more effective small-molecule inhibitors targeting YEATS4 should be developed to provide opportunities for drug design for cancer therapy. Further studies are needed to verify the potential interaction mechanisms between YEATS4 and other proteins in other cancers.