Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1

Feng Yang, Erhu Fang, Hong Mei, Yajun Chen, Huanhuan Li, Dan Li, Huajie Song, Jianqun Wang, Mei Hong, Wenjing Xiao, Xiaojing Wang, Kai Huang (+2 others)
2019 Cancer Research  
Circular RNAs (circRNA), a subclass of noncoding RNA characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. However, the functions and underlying mechanisms of circRNA in regulating Wnt/b-catenin signaling and cancer progression remain elusive. Here, we screen cis-acting circRNA generated by b-catenin (CTNNB1)/transcription factor 7like 2 genes and identify one intronic circRNA derived from CTNNB1 (circ-CTNNB1) as a novel driver of cancer
more » ... ogression. Circ-CTNNB1 was predominantly expressed in the nucleus, upregulated in cancer tissues and cell lines, and associated with unfavorable outcomes in patients with cancer. Circ-CTNNB1 promoted b-catenin activation, growth, invasion, and metastasis in cancer cells. Circ-CTNNB1 bound DEAD-box polypeptide 3 (DDX3) to facilitate its physical interaction with transcription factor Yin Yang 1 (YY1), resulting in the transactivation of YY1 and transcriptional alteration of downstream genes associated with b-catenin activation and cancer progression. Preclinically, administration of lentivirus-mediated short hairpin RNA targeting circ-CTNNB1 or a cell-penetrating inhibitory peptide blocking the circ-CTNNB1-DDX3 interaction inhibited downstream gene expression, tumorigenesis, and aggressiveness in cancer cells. Taken together, these results demonstrate cis-acting circ-CTNNB1 as a mediator of b-catenin signaling and cancer progression through DDX3-mediated transactivation of YY1. Significance: These findings reveal the oncogenic functions of a cis-acting circular RNA in b-catenin activation and cancer progression, with potential value as a therapeutic target for human cancers.
doi:10.1158/0008-5472.can-18-1559 fatcat:kewlbpqwh5hmlaw5q72fflhtfm