Circular RNAs (circRNAs) have been implicated to have important regulatory functions in chemical carcinogenesis via sponging microRNAs to regulate gene expression. Our study revealed a novel mechanism of circRNA in cadmium carcinogenesis through directly binding with protein. Here, we used cadmium-transformed human bronchial epithelial BEAS-2B cells to study the involvement and mechanism of circRNA in lung carcinogenesis caused by cadmium. By high-throughput sequencing, circSPAG16 was identified to be the most significantly downregulated circRNA in cadmium-transformed cells. CircSPAG16 was downregulated at Week 8, 12, 16, and 20 during cadmium-induced cell transformation. In addition, circSPAG16 overexpression prevented cadmium-induced transformation of BEAS-2B cells. Mechanistically, circSPAG16 inhibited the function of phosphatidylinositol 4-phosphate 5-kinase type-1 α (PIP5K1α) by binding with it. We demonstrated that PIP5K1α acted as an oncogene to activate Akt and promoted cancer hallmarks including proliferation, migration, invasion, and anchorage-independent growth in cadmium-transformed cells. CircSPAG16 overexpression inactivates PIP5K1α/Akt signaling in the transformed cells. Furthermore, PIP5K1α overexpression significantly rescued the inhibitory effects of circSPAG16 overexpression on pAkt and cancer hallmarks in cadmium-transformed cells. Collectively, our results revealed that circSPAG16 could prevent cadmium-induced transformation through binding with PIP5K1α to inactivate Akt. These results provide a novel regulatory mechanism of circRNA into carcinogenesis induced by cadmium.
Keywords: Akt; PIP5K1α; cadmium; carcinogenesis; circSPAG16.
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