Aurora kinase a phosphorylates and stabilizes UHRF1 to maintain DNA methylation and prostate cancer cell survival.

Abstract

Aberrant DNA methylation is a hallmark of prostate cancer (PCa) and plays a critical role in sustaining the epigenetic silencing of tumor suppressor genes. However, how oncogenic signaling pathways interface with the DNA methylation machinery remains poorly understood. In this study, we identify AURKA as a key regulator of global DNA methylation in PCa cells. AURKA depletion markedly reduces genomic 5-methylcytosine (5mC) levels, indicating its essential role in DNA methylation maintenance. Mechanistically, AURKA directly interacts with UHRF1-a crucial epigenetic regulator that recruits DNMT1 to hemimethylated DNA, and phosphorylates it at Ser76, thereby enhancing UHRF1 protein stability. AURKA depletion accelerates UHRF1 degradation via the ubiquitin-proteasome pathway, whereas AURKA overexpression stabilizes UHRF1 by suppressing its polyubiquitination. The phospho-deficient UHRF1 S76A mutant exhibits reduced stability and increased polyubiquitination, confirming that phosphorylation at Ser76 is critical for AURKA-mediated UHRF1 stabilization. Functionally, disruption of the AURKA-UHRF1 axis de-represses p16 and p21 and significantly impairs PCa cell proliferation; these effects are contingent upon UHRF1 phosphorylation, as only wild-type UHRF1, not the phospho-deficient S76A mutant, can rescue the observed phenotypic impairments. Collectively, our study reveals a previously unrecognized AURKA-UHRF1 signaling axis that links kinase activity to epigenetic maintenance. By phosphorylating UHRF1 at Ser76 and stabilizing its protein, AURKA sustains global DNA methylation and promotes PCa cell proliferation. These findings provide novel mechanistic insights into PCa biology and suggest that targeting this pathway may offer a promising therapeutic strategy.