UHRF1 Supports PARP1 Protein Stability and Ovarian Cancer Progression by Limiting PARP1 Polyubiquitination

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator with oncogenic activity, but its role in PARP1 protein homeostasis in ovarian cancer remains unclear. We assessed UHRF1 expression in public datasets and clinical specimens, tested UHRF1 depletion in ovarian cancer cells and mouse models, and examined UHRF1-PARP1 association, protein turnover, ubiquitination, and rescue. UHRF1 was elevated in ovarian tumor samples, and high expression was associated with adverse outcomes in the institutional tissue-microarray cohort. UHRF1 depletion reduced cell growth and migration, increased apoptosis, and reduced endpoint xenograft weight and volume. UHRF1 is associated with PARP1; its depletion reduced PARP1 protein without changing its mRNA, shortened its apparent half-life, and increased total PARP1-associated polyubiquitin. Re-expression of full-length UHRF1, but less effectively the TTD-deletion construct, restored PARP1 association and stability. In separate experiments, RNF4-targeting siRNA attenuated PARP1 loss and ubiquitination associated with UHRF1 depletion. Together, these findings identify UHRF1 as a regulator of PARP1 protein stability in ovarian cancer models and support contributions of the TTD-containing region and RNF4 to this regulation.