PCBP2 Mediates Olaparib Resistance in Breast Cancer by Inhibiting m6A Methylation to Stabilize PARP1 mRNA
Zhaochang Qi, Lifang He, Zemei Xu, Xi Luo, Likeng Ji, Chuqi Lin, Armando E. Giuliano, Xiaojiang Cui, Zihao Deng, Jundong Wu, Stanley L. Lin, Yu Cui
Abstract
Base excision repair (BER), a critical pathway for repairing DNA single-strand breaks, is mediated by PARP, which plays a pivotal role in maintaining genomic stability. Targeting PARP with PARP inhibitors (PARPi) has emerged as an effective strategy for treating BRCA-mutated breast cancers characterized by homologous recombination deficiency. However, PARPi resistance remains a major challenge in the treatment of BRCA-mutated breast cancer. Using bioinformatics analysis and cellular-level experiments, we discovered that the RNA-binding protein PCBP2 contributes to resistance to the PARPi olaparib in BRCA-mutated breast cancer by increasing PARP1 expression via interference with the m6A methylation machinery. PCBP2 was upregulated in olaparib-resistant cells, and PCBP2 overexpression in BRCA-mutated breast cancer cells increased resistance to olaparib and enhanced cell proliferation under treatment. Mechanistically, PCBP2 directly interacted with PARP1 mRNA, inhibiting m6A methylation and stabilizing the mRNA. PCBP2-mediated upregulation of PARP1 enhanced DNA repair activity, contributing to olaparib resistance. Together, these findings unveil a mechanism by which PCBP2 upregulates PARP1 to promote olaparib resistance in BRCA-mutated breast cancer, indicating that targeting this pathway could represent a therapeutic strategy to overcome PARPi resistance in breast cancer. SIGNIFICANCE: PCBP2-induced suppression of m6A methylation increases PARP1 to promote DNA damage repair and confer resistance to olaparib in BRCA-mutated breast cancer, making PCBP2 a potential therapeutic target to enhance PARP inhibitor sensitivity.