Targeting UHRF1 induces regression of aggressive mantle cell lymphoma

Although targeting the ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) has shown promise in treating a number of diseases, its function in mantle cell lymphoma (MCL) and its regulatory connection to SOX11 are yet unknown. Our study showed that UHRF1 is markedly upregulated in MCL, and this overexpression is associated with a poorer overall survival rate in MCL patients. Furthermore, in clinical MCL specimens, UHRF1 showed a positive correlation with the expression of SOX11 and Ki-67. In vitro, UHRF1 knockdown induced apoptosis and caused G2/M-phase arrest while functionally suppressing MCL cell motility, invasion, and proliferation. In MCL xenograft models, UHRF1 silence significantly delayed tumor development, and pharmacological targeting UHRF1 with CM272 effectively inhibited MCL progression with a tolerable safety profile. Mechanistically, SOX11 drives the transcriptional activation of UHRF1 by directly binding to its promoter region. Our results reveal that the SOX11-UHRF1 regulatory axis is a critical modulator of tumor cell growth and proliferation and identify UHRF1 as a key oncogenic driver in MCL. Additionally, CM272's antitumor effect was validated in preclinical MCL animal models while exhibiting an acceptable safety profile.