UHRF1 Is a Promising Therapy Target in Aggressive Mantle Cell Lymphoma

Backgrounds: Therapy resistance and recurrent relapses continue to be significant challenge in the management of mantle cell lymphoma (MCL), which cannot be explained by genetic alone. Discovering drugs that can successfully correct epigenetic changes is a promising strategy to address the inadequate therapeutic response in MCL. Epigenetic regulator ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is aberrantly expressed in many human diseases and correlated with disease progression, but its function in MCL remains unclear.

Methods: Through integrative analyses of the gene-expression profile and clinical parameters, UHRF1 was screened as a potential epigenetic therapy target in MCL patients. The pro-tumor function of UHRF1 was demonstrated by in vitro and in vivo experiment. The anti-tumor effect and safety of CM272, a functional inhibitor of UHRF1, was assessed in MCL xenograft animal model.

Results: UHRF1 was highly expressed and positively correlated with Ki67 expression in MCL tissues samples. UHRF1-high expression predicted poor prognosis in MCL patients. Knockdown of UHRF1 inhibited MCL cell proliferation, migration and invasion whereas induced MCL cell apoptosis and cell cycle arrest. Administration of mice with CM272 significantly inhibited MCL progression and no obvious treatment-related side effects in liver and renal.

Conclusion: Our study demonstrated that UHRF1 signaling involved in MCL tumorigenesis and progression, and provides a novel insight for therapeutic interventions in MCL by targeting UHRF1.

No relevant conflicts of interest to declare.