CircRHOBTB3 suppresses MAOA by promoting cytoplasmic retention of NONO to inhibit prostate cancer proliferation and metastasis

Abstract

Prostate cancer (PCa) is one of the most prevalent malignant tumors affecting men. Metastatic PCa is generally considered incurable. Circular RNA (circRNA) is a distinct class of RNA implicated in the tumorigenesis and development of various cancers, including PCa. However, the specific role and underlying molecular mechanisms of circRNA in PCa remain poorly understood. This study identifies hsa_circ_0007444, generated from the back-splicing of exons 6–7 of the Rho Related BTB Domain Containing 3 (RHOBTB3) gene and named as circRHOBTB3, as being downregulated in PCa. Low expression of circRHOBTB3 correlates with elevated pathological T stage, clinical M stage, and D'Amico grade. Functionally, circRHOBTB3 inhibits PCa cell proliferation and metastasis both in vitro and in vivo. Mechanistically, circRHOBTB3 binds to the non-POU domain-containing octamer-binding protein (NONO), a transcription factor for monoamine oxidase A (MAOA), sequestering NONO in the cytoplasm and preventing it from upregulating MAOA transcription. This results in decreased MAOA expression, ultimately suppressing PCa cell proliferation and metastasis. Furthermore, the RNA binding protein serine/arginine-rich splicing factor 9 specifically interacts with AluSx and AluJb, inhibiting circRHOBTB3 circularization. In conclusion, this study identifies circRHOBTB3 as a tumor suppressor with potential to be a promising clinical biomarker and therapeutic target for metastatic PCa.