Sevoflurane suppresses colorectal cancer malignancy by modulating β-catenin ubiquitination degradation via circSKA3

Abstract

Background: Sevoflurane (SEV), a commonly used inhalational anesthetic, reportedly inhibits colorectal cancer (CRC) malignancy, but whether SEV can inhibit the malignancy of CRC by regulating circular RNAs (circRNAs) remains unclear. Therefore, we aimed to identify specific circRNAs that may be affected by SEV and to investigate their functional roles in CRC.

Methods: RT-qPCR was employed to detect the expression of circRNAs and mRNAs in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to determine the location of circSKA3. Protein expression was assessed by western blot analysis. Function-based in vitro and in vivo experiments, including CCK-8, colony formation, transwell, and apoptosis assays and mouse xenograft tumor models, were conducted using circSKA3-knockdown and circSKA3-overexpression cell lines. RNA immunoprecipitation, RNA pull-down and mass spectrometry analyses were performed to explore the related mechanism.

Results: Our findings revealed that SEV could inhibit CRC cell activity, proliferation and migration and promote apoptosis in CRC cells. We found that circSKA3 was upregulated in CRC and associated with poorer survival and that its expression could be reduced by SEV. The overexpression of circSKA3 reversed the effects of SEV on inhibiting cell activity, proliferation and migration and promoting apoptosis. The mechanistic analysis revealed that circSKA3 could bind to the ARM structural domain of β-catenin and thereby disrupt its interaction with the CK1/GSK3β/β-TrCP1 destruction complex, resulting in the ubiquitinated degradation of β-catenin and the activation of Wnt/β-catenin signaling. In addition, SEV downregulated circSKA3 in vivo to inhibit tumor growth.

Conclusions: All the results showed that SEV could inhibit CRC progression via circSKA3 by increasing β-catenin ubiquitination degradation.

Keywords: CircRNA; Colorectal cancer; Sevoflurane; Wnt signaling; β-catenin.