Identification of circRBM39 as a tumor suppressor in breast cancer

Circular RNAs (circRNAs) have emerged as pivotal players in both physiology and human cancers. However, their modes of action in breast cancer remain elusive. Herein, we have identified a significantly downregulated circRNA, termed circRBM39, in breast cancer specimen compared with adjacent non-tumor tissues. Gain- and loss-of-function assays demonstrate that circRBM39 inhibits breast tumorigenesis through the impairment of DNA damage response in vitro and in vivo. Mechanistically, circRBM39 directly interacts with replication protein A2 (RPA2) and decreases the RPA2 protein level via facilitating the HERC2-mediated ubiquitination, thereby disrupting homologous recombination repair. Importantly, administration of in vitro synthesized circRBM39 exhibits substantially repressive effects on breast cancer progression, sensitizes breast cancer cells to PARP inhibition, and renders them susceptible to synthetic lethality in a subcutaneous breast tumorigenesis model. Collectively, our findings demonstrate the tumor-suppressive roles of circRBM39 in breast cancer, and highlight the interplay between circRNA and genome stability in cancers. Overall design: In an effort to investigate functional roles of circRNAs in breast cancer, we performed RNA sequencing (RNA-seq) of two-paired breast cancer specimen and adjacent non-tumor (NT) tissues to identify promising circRNA candidates. To further explore the functional mechanism of circRBM39 in breast cancer, we also performed polyadenylated RNA-seq in control and circRBM39 OE MDA-231 cells.