CircLRBA Promotes Epithelial-Mesenchymal Transition, Immune Evasion, Chemoimmunotherapy Resistance and Metastasis Through Stabilizing Twist1.

Abstract

Breast cancer (BC) is a malignant tumor with the highest incidence in women. Metastasis is the leading cause of BC-related death. Circular RNAs (circRNAs) play important roles in cancer progression and metastasis, therefore exploring its specific mechanism in BC metastasis has high value. However, the biological roles and potential mechanism of circRNAs in BC remain unclear. Here, a highly expressed circRNA circLRBA in BC tissues is identified using high-throughput sequencing, which is associated with pathological stage and poor overall survival. Functional assays show that circLRBA facilitates BC cell proliferation, invasion, migration, docetaxel (DTX) resistance, and inhibits the infiltration of CD8+ T cell in vitro and in vivo. Whereas circLRBA knockdown reveals opposite roles. Mechanistically, transcription factor Zeb1 promotes the generation of circLRBA. Importantly, circLRBA could competitively combine with E3 ubiquitin ligase SPOP to suppress the Twist1 ubiquitination degradation and enhances PD-L1 transcriptional activity, thus promoting EMT, immune evasion, chemoresistance and BC progression. This study highlights the oncogenic role of circLRBA in BC progression through its binding with SPOP to increases Twist1 stability, suggesting that circLRBA might serve as a promising biomarker and potential therapeutic target for BC.