Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway

• Published in: Genome Biology Vol. 20; no. 1; p. 84
• Main Authors: Liang, Wei-Cheng, Wong, Cheuk-Wa, Liang, Pu-Ping, Shi, Mai, Cao, Ye, Rao, Shi-Tao, Tsui, Stephen Kwok-Wing, Waye, Mary Miu-Yee, Zhang, Qi, Fu, Wei-Ming, Zhang, Jin-Fang
• Format: Journal Article
• Language: English
• Published: England BioMed Central 26.04.2019; BMC
• Subjects: Amino acids; Animals; beta catenin; beta Catenin - genetics; Bioinformatics; Carcinogenesis; Carcinoma, Hepatocellular - etiology; Cell activation; Cell growth; Cell Line, Tumor; Cell Movement; Circular RNA; Coding capacity; Cytoplasm; eukaryotic cells; Gene expression; Gene Knockdown Techniques; Glycogen Synthase Kinase 3 beta - metabolism; Hepatocellular carcinoma; Hepatocytes; hepatoma; Humans; Kinases; Ligands; Liver cancer; Liver Neoplasms - etiology; loci; messenger RNA; Mice, Nude; MicroRNAs; Mortality; neoplasm cells; Neoplasm Metastasis; Non-coding RNA; Online data bases; phenotype; Phenotypes; Phosphorylation; protein content; Proteins; Ribonuclease; RNA - metabolism; RNA, Circular; start codon; Stop codon; tissues; Transcription; Translation; translation (genetics); Tumorigenesis; Wnt pathway; Wnt protein; Wnt Signaling Pathway; β-Catenin; Circular RNA; Cell growth; Wnt pathway; Non-coding RNA; Coding capacity
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-019-1685-4

Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the β-catenin gene locus, circβ-catenin. Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma.