SETBP1-R54P mutation promotes malignant transformation of cadmium-induced 16HBE cells by down-regulating circ_0007095 expression

Abstract Some cancers are strongly associated with exposure to environmental carcinogens, and genetic and epigenetic alterations are crucial in carcinogenesis. However, the interaction between genetic mutations and epigenetic regulation in cancer development has not been sufficiently examined. Here, we investigated the roles of gene mutations and altered circRNA expression in the malignant transformation of human bronchial epithelial cells after continuous exposure to CdCl2 (10 µM). The circular RNA circ_0007095 was down-regulated, and the SETBP1-R54P single nucleotide variant (SNV) accumulated during Cd carcinogenesis. The decreased circ_0007095 expression enhanced CdCl2-induced cancer cell proliferation, migration and tumor formation, and the accumulation of SETBP1-R54P also promoted CdCl2-induced carcinogenesis. Mechanistic studies showed that SETBP1-R54P mutation promoted circ_0007095 degradation by activating the KLF4-PFKP axis in the RNA degradation pathway. SETBP1-R54P mutation promoted the malignant transformation of Cd-induced 16HBE cells by regulating circ_0007095 expression. Our findings emphasize the importance of the interaction between genetic variation and epigenetic regulation during environmental chemical carcinogenesis and advance understanding of cancer etiology.