Circular RNA circWBSCR22 facilitates colorectal cancer metastasis by enhancing CHD4's protein stability

Abstract

Widespread metastases continue to be a massive challenge for colorectal cancer (CRC) therapy and contribute to the high mortality rate in patients with CRC. Circular RNAs (circRNAs) are a novel group of endogenous RNAs identified as agents modulating tumorigenesis and aggressiveness with tissue heterogeneity. However, the biological functions of circRNAs in CRC metastasis remain largely unknown. Here, we identified that circWBSCR22, a novel circRNA back-spliced from the WBSCR22 pre-mRNA, was significantly elevated in CRC tissue compared with adjacent normal tissue. Further gain- and loss-of-function assays manifested that circWBSCR22 promotes epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo, which are mediated by the chromodomain helicase-DNA-binding protein 4 (CHD4) protein. Mechanically, circWBSCR22 binds directly to up-frameshift protein 1 (UPF1), an RNA binding protein recognized for its function in RNA surveillance, and hinders its role in directing CHD4 protein ubiquitination for degradation. Consequently, by stabilizing the CHD4 protein, circWBSCR22 hastens the development and metastasis of CRC. Therefore, our findings first delineate the oncogenic role and mechanism of circWBSCR22 in CRC growth and metastasis and its potential to serve as a therapeutic target for CRC.