A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer

Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (beta(1) integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination--independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.

Automated summary

The study identified dysregulated circPABPC1 in human hepatocellular carcinoma, which is preferentially lost in tumor cells and inhibits metastasis. It suppresses cell adhesion and migration by down-regulating a key integrin family member, ITGB1, through a unique degradation pathway. These findings provide a new understanding of circRNAs' role in cancer treatment.