circEZH2^E2/E3 is a dual suppressor of miR363/miR708 to promote EZH2 expression and prostate cancer progression

Abstract

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3′UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2‐repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression‐free and disease‐specific survival in PCa patients. These findings show a novel autoenhancing EZH2–circEZH2E2/E3‐miR363/miR708–EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management.

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…[147][148][149][150][151][152] Here, we summarized the important functions and related regulatory mechanisms of circRNAs involved in PCa (Table 3). [190] circ_0070512 Up Promotes progression miR-338-3p/Hedgehog signaling pathway [191] circSPON2 Up Promotes progression miR-331-3p/PRMT5 axis [192] circSMARCC1 Up Promotes progression miR-1322/CCL20/CCR6 axis [193] circSCAF8 Up Promotes growth and metastasis miR-140-3p/miR-335-LIF axis [194] circEZH2 E2/E3 Up Promotes progression EZH2-circEZH2 E2/E3 -miR363/ miR708-EZH2 regulatory loop [195] circHMGCS1 Up Promotes progression miR-205-5p/ErBB3 axis [196] circARHGEF28 Down Inhibits progression miR-671-5p/LGALS3BP/NF-κB axis [121] circ_0063329 Down Inhibits growth and metastasis miR-605-5p/TGIF2 axis [197] circEPHA3 Down Inhibits progression miR-513a-3p/BMP2 axis [198] circDHRS3 Down Inhibits progression miR-421/MEIS2 axis [199] circPHF16…”