Oncogenic circPRRC2B regulates redox homeostasis via stabilizing TALDO1 protein of the pentose phosphate pathway in esophageal squamous cell carcinoma.

It remains largely unclear whether oncogenic super-enhancers (SEs) can drive expression of circular RNAs (circRNAs). In this study, we for the first time profiled the comprehensive circRNA landscapes of esophageal squamous cell carcinoma (ESCC) after suppressing genome-wide SE activities. We identified a novel SE-driven circPRRC2B, as the product of back-splicing of exons 2, 3, 4 and 5 of PRRC2B pre-mRNA, which was controlled by RNA binding protein HuR. Indeed, SE drives high levels of PRRC2B transcription, promotes production of PRRC2B pre-mRNAs, boosts back-splicing of PRRC2B pre-mRNAs, and elevates circPRRC2B expression. ETS1 acts as a key transcriptional factor in SE-driven PRRC2B transcription and circPRRC2B biogenesis. Interestingly, circPRRC2B, but not PRRC2B, could promote proliferation, invasion and metastasis of ESCC in vitro and in vivo. Mechanistically, circPRRC2B binds to TALDO1 and enhances BAP1-mediated TALDO1 de-ubiquitination in ESCC cells. Therefore, circPRRC2B stabilizes and sustains high expression of TALDO1, activates the pentose phosphate pathway (PPP), elevates the glutathione levels via supplying more NADPH via the PPP, inhibits production of reactive oxygen species in mitochondrion, maintains cellular redox equilibrium, and, thus, leads to cancer progression. Importantly, we developed antisense oligonucleotides targeting circPRRC2B which exhibited remarkable inhibition of ESCC growth. Our findings highlighted circPRRC2B as a key target preserving the PPP metabolic flux and redox homeostasis of malignant cells, thereby offering insight into developing novel therapeutics for cancers.