Circular RNA circERBB2 Promotes Tumorigenesis via the miR‐1587/CBX2 Axis and Epigenetic Silencing of PTEN in Bladder Cancer Cells

Bladder cancer (BLCA) remains difficult to manage because of frequent recurrence and limited effective treatment options. This study investigated the role and mechanism of the ERBB2‐derived circular RNA circERBB2 in BLCA. Public circRNA data sets and a 96‐pair clinical cohort were analyzed to identify dysregulated circRNAs, followed by RT‐qPCR, gain‐ and loss‐of‐function assays, and xenograft experiments to assess circERBB2 function. FISH, AGO2‐RIP, and dual‐luciferase reporter assays were used to examine the circERBB2/miR‐1587 interaction, while target prediction and rescue experiments identified chromobox 2 (CBX2) as a downstream effector. RNA sequencing and Western blotting linked this axis to PI3K/AKT/mTOR signaling and PTEN regulation. Co‐immunoprecipitation and ChIP‐qPCR further showed that CBX2 associates with EZH2 and promotes H3K27me3 enrichment at the PTEN promoter. CircERBB2 was upregulated and stable in BLCA, and higher expression was associated with adverse clinicopathological features and poorer prognosis; its silencing inhibited proliferation, migration, invasion, and xenograft growth. Mechanistically, circERBB2 relieved miR‐1587‐mediated repression of CBX2, facilitating EZH2‐dependent PTEN silencing and pathway activation. These findings define a circERBB2/miR‐1587/CBX2/PTEN regulatory axis and support circERBB2 as a potential biomarker and therapeutic target in BLCA.