UHRF1-mediated HIF-1α stabilization promotes ovarian cancer through metabolic reprogramming and angiogenesis

Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is an important epigenetic regulatory factor that is highly expressed in various cancers and participates in tumorigenesis and progression. However, the role and molecular mechanisms of UHRF1 in ovarian cancer (OC) remain unclear. Through survival analysis, cellular functional experiments, and animal studies, we identified UHRF1 as a key gene influencing OC progression and prognosis. Hypoxia-inducible factor-1 (HIF-1α), a well-known pro-cancer molecule, undergoes classic degradation via the ubiquitin-proteasome pathway. We discovered that UHRF1 interacts with HIF-1α, affecting its hydroxylation level, thereby inhibiting HIF-1α polyubiquitination and degradation. Functional experiments revealed that knocking down HIF-1α in stable UHRF1-overexpressing cell lines significantly reversed the malignant phenotype of OC cells. Furthermore, UHRF1 can also regulate the expression of key downstream molecules such as GLUT1, HK2, LDHA, and VEGFA by modulating HIF-1α, thus influencing tumor cell metabolism and angiogenesis. In summary, our findings suggest that UHRF1 plays a crucial role in the development of OC by regulating the expression of HIF-1α.