CircHECTD1 Promotes Cholangiocarcinoma Progression Through Interaction With SFPQ to Induce Autophagy

ABSTRACT

Cholangiocarcinoma (CCA) constitutes a highly malignant tumor type demonstrating rising global incidence rates. Circular RNAs (circRNAs), characterized by their covalently bonded single‐stranded loop configuration, have been identified as functional regulators across various cancer types. Previous studies have suggested circHECTD1's involvement in tumor processes, but its specific contributions and molecular pathways in CCA progression, particularly regarding autophagy regulation, remain unclear. Experimental data demonstrated significant upregulation of circHECTD1 in CCA cell lines, along with notable stability against RNase‐mediated breakdown. From a functional perspective, increased circHECTD1 expression stimulated tumor cell growth, motility, invasive capacity, and autophagy processes, while triggering autophagosome formation. Mechanistically, circHECTD1 served as a molecular platform for the splicing factor SFPQ (proline‐ and glutamine‐rich), facilitating SFPQ's binding to the ATG12 promoter regulatory region and enhancing the expression of ATG12 mRNA, resulting in increased transcriptional activity and enhanced mRNA durability, which in turn stimulated the autophagic process. When SFPQ was experimentally downregulated, this effect was diminished. Conversely, when autophagy was pharmacologically inhibited, the oncogenic effects mediated by circHECTD1 were effectively counteracted. These observations suggest that circHECTD1 plays a crucial role in the progression of CCA by forming a complex with SFPQ, which subsequently enhances both the transcription of ATG12 and the stability of ATG12 mRNA, thereby promoting autophagy and tumor progression.