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

backgroundEven 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.

methodsHere, 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.

resultsWe 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.

conclusionsThis study shows that transcriptional programs associated with oncogenic pathways can be activated in differentiated mammalian cells without predisposing mutations in oncogenes or epigenetic regulators.