Background

Bladder cancer (BC) is the most common type of urinary cancer worldwide, with high recurrence and mortality [1]. Although numerous novel treatment regimens have been applied in the recent decade, no radical improvement in prognosis has been achieved in clinical practice. To date, local or systemic chemotherapy using widely accepted drugs is still the best therapeutic intervention to assist in surgery for BC treatment [2]. Although immune checkpoint inhibitors (ICIs) have emerged as an effective alternative for managing advanced disease and have shown durable responses in a subset of patients with BC [3], unfortunately, the overall response rate is only approximately 15–25% [4]. To improve the outcome of patients with BC, we need to urgently explore more therapeutic targets and identify appropriate drugs for treating BC [5].

Unbalanced methylation is gradually being accepted as a potential driver in human cancers [6]. Although lysine methyltransferases are widely known to regulate gene expression coupled with BC development, arginine methyltransferases and their roles in BC remain obscure [7]. Protein arginine methyltransferases (PRMTs) are enzymes that transfer a methyl group from S-adenosyl-L-methionine (SAM) to the substrate arginine side chain and can be categorized into different subtypes based on their catalytic routes [8]. Arginine methylation disorder has been reported to be prevalent in breast, lung, and colon cancers and leukemia [9]. Most PRMTs have been implicated in the regulation of cancer-associated epigenetics and chromatin transcription signaling, RNA metabolism, and DNA repair [10]. Recent reports have shown that some PRMTs play indispensable roles in regulating BC and are closely related to the proliferation, invasion, and poor prognosis of the disease [11]. However, no systematic analysis on PRMTs in BC has been performed to date, and the type of PRMT that specifically promotes the development of BC remains unknown.

The roles of PRMT enzymes in numerous diseases have spurred significant interest in targeting them pharmacologically [12]. Among these enzymes, including EPZ015866, EPZ015666, GSK3326595, and LY-283, the development of PRMT5 inhibitors is the most attractive approach [13,14,15,16]. Although some inhibitors have shown an inhibitory effect on PRMT5 enzyme activity and function, their toxicity and therapeutic effect are still being investigated [17].

Kava has been used for treating inflammatory bladder diseases for more than 100 years, and chalcones are the main classes of compounds identified from kava extracts, including flavokawain A, B, and C [18, 19]. These chalcones have also been found to have strong anti-tumor activity against various cancers, such as colon, lung, gastric, and breast cancers [20,21,22,23,24,25]. FKA, in particular, has a unique anti-cancer activity against urinary tract tumors [26]. Studies have demonstrated that FKA has the strongest anti-BC activity among the kava extracts discovered till date [27].

In previous studies, FKA could induce apoptosis in BC cells via the involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathways [27]. In addition, FKA could induce a G2-M arrest in the bladder and prostate cancer cells [47, 48]. The combination of PRMT5 inhibitors with other regimens has also received great attention. NCT02783300 is evaluating PRMT5 inhibitors with immunotherapy like PD-1 antibody and NCT04794699 is testing the synthetic lethal effect of PRMT5 inhibitor with MTAP defect [49]. In our study, we also determined the combined effect of PRMT5 with some clinically used drugs. Inhibiting PRMT5 increased the chemotherapeutic effect of cisplatin and gemcitabine, and co-treatment of PRMT5 and EGFR inhibitor significantly inhibited cancer cell growth. The encouraging results of this work indicated that PRMT5 was a suitable target for develo** combined therapies with other drugs [50]. Further exploring its synergetic effect with PARP inhibitors, immunotherapeutic antibodies, or chemotherapeutic drugs is worthy for further research.

Conclusions

In conclusion, we systematically analyzed the role of the PRMT family in BC and confirmed that PRMT5 was highly correlated with the malignant properties of BC and could be an ideal epigenetic therapeutic target. As the first natural small molecule inhibitor of PRMT5, FKA had a strong inhibitory effect on BC and warrants further development to translate it into clinical applications.