PRMT5 is a primary type II arginine methyl transferase that forms a prominent methylosome complex with distinctive binding oligopeptides, such as the WD (Trp-Asp) repeat-containing 50-kilodalton methylosome protein (MEP50). PRMT5 requires the existence of diverse substrate adapters such as rio-domain-containing protein 1 (RioK1), chloride channel nucleotide-sensitive 1A protein (pIC1n) and cooperator of PRTM5 (COPR5) to detect and catalyze the SDMA on histone and non-histone proteins via PTMs [31,32,33]. PRMT5′s structure consists of a triphosphate isomerase (TIM) barrel, an intermediate Rossmann-fold, and a C-terminal β-barrel [34]. Four PRMT5 units generate a hetero octameric complex by binding with four MEP50s (Figure 1). Studies have demonstrated that PRMT5 alone has minimal methyltransferase activity; it must be complexed with MEP50 to achieve normal catalysis of SDMA on proteins [35]. This could be because MEP50 enhances the stability of PRMT5 for a long time by binding with proteins and acting as a metastable cofactor.

PRMT5 plays a key role in cell functions and processes by regulating the methylation of cellular proteins, which affects oncogenic cellular processes such as cell proliferation and differentiation [29,30,36]. PRMT5 regulates these processes by modifying gene expression to stabilize histones H4R3, H3R2, H3R8, and H2AR3 and non-histone proteins via the SDMA process [37,38]. An extensive range of nonhistone proteins have also been revealed as PRMT5 substrates, including androgen receptor (AR), EGFR, GATA4, C-MYC, N-MYC, IL-2, E2F1, GM130, HOXA9, KLF4, KLF5, NOTCH, NFkB(p65), PDCD4, POLR2A, P53, RAF proteins, SPT5, SREBP1a, Sm proteins, nucleolin, and others [12,36,39,40,41,42,43,44,45,46,47,48,49,50,51,52]. In addition, some substrates such as certain nonhistone oncogenic transcription factors are symmetrically dimethylated by PRMT5. PRMT5-regulated cellular processes are shown in Figure 2. The importance of arginine methylation by PRMT5 in cancer progression has only recently become apparent [17]. PRMT5 knockout mice exhibited embryonic lethality, demonstrating the role of PRTM5 in embryonic development and crucial biological functions. In mouse embryonic stem cells (ESCs), PRMT5 maintains pluripotency, whereas in human ESCs, it influences only proliferation [53,54]. PRMT5 is needed for neural stem cell persistence and its deletion causes premature death of the mouse by disrupting the development of the central nervous system [55]. PRMT5 promotes SWI/SNF-mediated chromatin remodeling and controls the process of myogenesis. Deletion of PRMT5 causes an obstacle in developmental processes, uncontrolled proliferation, and impairment of adult tissue differentiation [53,54,55,56,57,58]. Notably, PRMT5 is overexpressed in a number of cancers, including melanoma, multiple myeloma, lymphoma, glioblastoma, breast, lung, pancreas, prostate, ovarian, and colorectal cancers, and high expression of PRMT5 often correlates with poor patient clinical outcomes [38,59]. Organ-specific functions of PRMT5 are shown in Table 1. The higher expression of PRMT5 in cancer is thought to epigenetically suppress tumor suppressor and cell cycle genes [17,60]. Recently, the association of PRMT5 with MYC was found in numerous cancers, including brain tumors such as glioblastoma; this association creates abnormalities in MYC function [61,62,63]. Consequently, PRMT5 has been recognized as an oncogenic function and has received extensive interest as a potential target for better clinical outcomes. To this end, numerous potent therapeutic agents have been developed to inhibit PRMT5 and their antitumor effects are now being assessed in preclinical models and clinical trials [27,64].

Cytosolic and nuclear localization of PRMT5 helps to determine its role in the cell. PRMT5 is predominantly localized in the cytoplasm in lung [65], prostate [66], and melanoma cancer [67]. Diffused cellular localization of PRMT5 was confirmed in both the cytoplasm and the nucleus of brain tumor glioblastoma cells [61]. Cytoplasmic and nuclear localization of PRMT5 has also been confirmed in various preclinical mouse models and primary human cancer tissues [68]. In adult mice, PRMT5 is expressed predominantly in the nucleus of the neurons in the cerebrum and spinal cord [55]. Han et al. demonstrated the high expression of PRMT5 as a marker of malignant progression in glioblastoma and its crucial role in tumor growth [63]. Our lab recently analyzed the localization of the PRMT5 in tumor tissues of medulloblastoma patients as well as in MYC-amplified cell lines. PRMT5 demonstrated predominantly nuclear localization in both HD-MB03 and primary tumor cells [22].

Epigenetic deregulation plays a key role in medulloblastoma tumorigenesis, especially in aggressive Group 3 and Group 4 medulloblastomas [99,100,101,102], where germline mutations in known cancer predisposition genes are rare. Indeed, epigenetic deregulator or chromatin modifiers, including histone acetylase or methylation/methyltransferase activities, are very common in Group 3 and 4 medulloblastomas compared to other subgroups. This emphasizes the need to discover and understand the pertinent mechanisms of epigenetic regulation or PTMs and the corresponding therapeutic targets. We recently reported that PRTM5 is a critical regulator MYC oncoprotein in an MYC-amplified (Group 3) medulloblastoma [22]. We found that high levels of PRMT5 not only mirror MYC expression but also correlate with poor outcomes in Group 3 medulloblastoma patients. Mechanistically, we showed that PRMT5 stabilizes the MYC protein by physically interacting with it, raising the intriguing possibility that PRMT5 can regulate MYC function at both the transcriptional and translational/post-translational levels. The exact MYC oncogenic programs regulated by PRMT5 in medulloblastoma are largely unknown. Therefore, exploring the regulation of MYC-driven oncogenic progresses by PRMT5 is crucial to identify effective therapeutics for these high-risk patients.

The involvement of PRMT5 has been verified in the epigenetic regulation of chromatin complexes following interaction with numerous proteins, including transcription factors [42], and their activities are dysregulated in various cancers [59]. In recent studies, high levels of PRMT5 and MYC corelate with glioma malignancy [61,62,63]. Furthermore, PRMT5 is physically associated with N-MYC (an MYC homologue) and enhances the stability of N-MYC in neuroblastoma cells [51]. Nonetheless, the function of PRMT5 and its interaction with MYC in MYC-driven medulloblastoma have not been fully investigated. Favia et al. reported that the association of PRMT1 and PRMT5 with MYC in glioblastoma stem cells resulted in MYC being dimethylated symmetrically and asymmetrically by both enzymes, respectively [103]. MYC-driven cellular processes resulting from symmetric dimethylation by PRMT5 are shown in Figure 3. The colocalization of PRMT5 and MYC suggests that PRMT5 forms a complex with MYC and supports its stabilization in MYC-amplified medulloblastoma cells. This physical interaction of PRMT5 and MYC implies a potential role of PRMT5 in medulloblastoma tumorigenesis.

Highly expressed PRMT5 stabilizes MYC and promotes its expression in medulloblastomas. Studies support the predictive value of PRMT5 overexpression as a biomarker for aggressive tumorigenesis in cancer patients. Knockdown of PRMT5 in medulloblastoma cells suppresses cell growth by diminishing MYC stability, supporting the functional role of the PRMT5–MYC interaction complex in medulloblastoma [22]. Since MYC and PRMT5 co-expression and colocalization were observed in the nucleus, PRMT5 could also regulate MYC function at the transcriptional level. Further studies are needed to investigate PRMT5’s roles in the regulation of the transcription and translation of MYC.

PRMT5 is a stemness factor crucial in maintaining the balance between quiescence, proliferation, and generation for cancer stem cells and non-cancer cells. The role of PRMT5 in stemness has been demonstrated in embryonic (ESCs) and neural stem cells (NSCs) [53,72,104]. Provided that NCCs or cancer stem cells have a great influence on medulloblastoma recurrence and tumorigenesis, there might be a role for PRMT5 in regulating the self-renewal of tumor initiation in medulloblastoma. Recently, the methylation of stemness factor KLF-4 (Kruppel-like factor-4) by PRTM5 was shown in breast cancer [96]. This methylation leads to KLF4 protein stabilization, promoting tumorigenesis. In another study, researchers synthesized a novel compound that has the potency to inhibit PRMT5, disrupt the interaction of PRMT5 and KLF4, and suppress breast cancer development [105]. KLFs are evolutionarily conserved zinc-finger-associated transcription factors with distinct regulatory functions in cell growth, proliferation, and differentiation. Moreover, PRMT5 interacts with KLF5 (another member of KLF family proteins) and accelerates its dimethylation, a mechanism that depends on methyltransferase activity [81]. Further investigation to understand the mechanism of PRTM5–KLF4/KL5 interactions could uncover another new strategy to elucidate therapeutic targets for MYC-amplified medulloblastoma.

PRMT5 inhibitors have been proven to prevent the growth of cancerous cells in vitro and in vivo. Many PRMT5 inhibitors have entered clinical trials for the treatment of multiple types of cancer [34,106,107]. The pharmacological effects of these inhibitors with their targets in various cancers are summarized in Table 2, and details about corresponding clinical trials are given in Table 3.