Xiaowei Wu

RUNX1-IT1 acts as a scaffold of STAT1 and NuRD complex to promote ROS-mediated NF-κB activation and ovarian cancer progression

Dysregulated expression of long-stranded non-coding RNAs is strongly associated with carcinogenesis. However, the precise mechanisms underlying their involvement in ovarian cancer pathogenesis remain poorly defined. Here, we found that lncRNA RUNX1-IT1 plays a crucial role in the progression of ovarian cancer. Patients with high RUNX1-IT1 expression had shorter survival and poorer outcomes. Notably, knockdown of RUNX1-IT1 suppressed the proliferation, migration and invasion of ovarian cancer cells in vitro, and reduced the formation of peritoneum metastasis in vivo. Mechanistically, RUNX1-IT1 bound to HDAC1, the core component of the NuRD complex, and STAT1, acting as a molecular scaffold of the STAT1 and NuRD complex to regulate intracellular reactive oxygen homeostasis by altering the histone modification status of downstream targets including GPX1. Consequently, RUNX1-IT1 activated NF-κB signaling and altered the biology of ovarian cancer cells. In conclusion, our findings demonstrate that RUNX1-IT1 promotes ovarian malignancy and suggest that targeting RUNX1-IT1 represents a promising therapeutic strategy for ovarian cancer treatment.

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.