PRMT7‐mediated arginine methylation of FOXK activates Wnt/β‐catenin signalling to drive doxorubicin resistance in diffuse large B‐cell lymphoma

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Abstract Background Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in diffuse large B‑cell lymphoma (DLBCL) treatment, yet its clinical efficacy is often compromised by drug resistance. Protein arginine methyltransferase 7 (PRMT7) is a methyltransferase implicated in tumourigenesis and cancer progression. However, its precise role and underlying mechanisms in DLBCL progression and doxorubicin resistance remain unclear. Methods We analysed PRMT7 expression in DLBCL cell lines and patient specimens using bioinformatic databases, western blotting, reverse Transcription Polymerase Chain Reactionand immunohistochemistry. Functional studies were performed in DLBCL cell lines through CRISPR/Cas9‑mediated knockout and overexpression systems, combined with in vitro assays for proliferation, apoptosis and doxorubicin sensitivity, as well as in vivo xenograft models. Mechanistically, co‑immunoprecipitation, arginine methylation assays and immunofluorescence were employed to characterise the PRMT7–Forkhead box K (FOXK)1/2–Dishevelled Segment Polarity Protein 2 (DVL2) axis and its modulation of Wnt/ (beta) β‑catenin signalling. In addition, we designed and evaluated FOXK‑methylation‑competitive inhibitory peptides for their capacity to sensitise DLBCL cells to doxorubicin. Results Our study revealed that PRMT7 is upregulated in DLBCL and promotes both tumour proliferation and doxorubicin resistance. Conversely, knockdown of PRMT7 inhibited DLBCL cell proliferation and enhanced sensitivity to doxorubicin. Mechanistically, PRMT7 catalyses arginine methylation of FOXK1 at arginine (R) 191 and FOXK2 at R144, which markedly increases their binding affinity for DVL2 and facilitates DVL2 nuclear translocation. This event leads to constitutive activation of the Wnt/β‑catenin signalling pathway. Importantly, we developed a FOXK‑derived peptide that competitively inhibits FOXK methylation, suppresses Wnt/β‑catenin signalling and significantly potentiates the antitumour efficacy of doxorubicin in DLBCL. Conclusion Our findings indicate that the PRMT7/FOXK/DVL2/Wnt‐β‐catenin axis serves as a novel driver of DLBCL progression and doxorubicin resistance. Targeting the PRMT7–FOXK methylation interface may offer a potential therapeutic approach for overcoming doxorubicin resistance in DLBCL, although further validation in clinical settings is warranted. Key points Upregulated PRMT7 drives DLBCL progression and doxorubicin resistance PRMT7 methylates FOXK1 at arginine 191 and FOXK2 at arginine 144 FOXK1/2 methylation enhances interaction with DVL2 and promotes nuclear translocation FOXK1/2 methylation dactivate Wnt/ß-catenin signaling through DVL2 nuclear entry A novel peptide inhibitory blocks FOXK1/2 methylation and restores doxorubicin sensitivity