YAP derived circ-LECRC functions as a “brake signal” to suppress hyperactivation of oncogenic YAP signalling in colorectal cancer

Abstract

Accumulating evidence indicates that circular RNAs (circRNAs) play vital roles in tumorigenesis by modulating gene expression. However, the molecular mechanisms underlying the functions of circRNAs remain largely unknown. Here, we demonstrated that a Yes1 associated transcriptional regulator (YAP1)-derived circRNA, circ-LECRC (circRNA low expressed in CRC), was significantly downregulated in colorectal cancer (CRC). High expression of circ-LECRC positively correlated with a lower TNM stage and good prognosis in CRC patients. Circ-LECRC overexpression significantly inhibited CRC cell proliferation, migration, and invasion and promoted apoptosis (P < 0.05). Additionally, we performed xenograft and lung metastasis experiments by injecting CRC cells into nude mice to mechanistically demonstrate that circ-LECRC directly binds to miR-135b-5p and relieve the suppression of its target, Krüppel-like factor 4 (KLF4). Furthermore, we found that both circ-LECRC and KLF4 inhibited YAP1 hyperactivation, which downregulates the expression of the downstream genes of the YAP1 pathway, such as EGFR, MYC, BIRC5, and CTGF. In summary, circ-LECRC regulates KLF4 expression by functioning as a competing endogenous RNA and serves as a “brake signal” to suppress hyperactivation of oncogenic YAP signalling, leading to tumour growth inhibition in CRC.