SATB2 dysregulation generates a novel circular RNA and drives KRAS-like transcriptional reprogramming and transformation-associated phenotypes

BACKGROUND: Even though epigenetic factors contribute to oncogenesis, most human cancer models still assume that disease originates from driver DNA mutations. Thus, it is still unclear if non-genetic mechanisms are sufficient to trigger malignant transformation. Special AT-rich binding protein 2 (SATB2) is a chromatin organizer that brings distal DNA elements into close proximity, thus remodeling chromatin structures to reprogram cell-specific and/or developmentally sensitive gene networks. METHODS: Here, we chronically exposed human bronchial lung epithelial cells to ≤ 2 µM inorganic arsenic, and then used biochemical, molecular, and phenotypic assays to understand how changes in SATB2 expression and chromatin structure relate to oncogenic transformation. RESULTS: We discovered that SATB2 generates a co-expressed circ3915 RNA that can be translated into a peptide that co-localizes with SATB2 in and around the nuclear membrane. Ectopic SATB2 or circ3915 expression rearranged global chromatin accessibility, generated KRAS- and NFE2L2-like oncogenic gene expression patterns, and induced oncogenic phenotypes and KRAS-like transcriptional programs in lung epithelial cells without iAs exposure or engineered driver mutations. SATB2 and circ3915 transcripts persisted through the epithelial-to-mesenchymal transition and were co-regulated in human LUAD and LUSC tumors and adjacent normal tissue. CONCLUSIONS: This study shows that transcriptional programs associated with oncogenic pathways can be activated in differentiated mammalian cells without predisposing mutations in oncogenes or epigenetic regulators.