SATB2 and circ3915 RNA chromatin dysregulation drive KRAS-like oncogenic transformation

Abstract

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. Here, we discover that SATB2 generates a co-expressed circ3915 RNA that is translated into a peptide and co-locates with SATB2 in the cell nucleus. Ectopic SATB2 or circ3915 over- expression rearranges global chromatin accessibility, generates KRAS- and NFE2L2-like oncogenic gene expression patterns, and transforms lung epithelial cells independent of driver mutations. Thus, oncogenic pathways can be activated in mammalian cells without pre-disposing mutations in oncogenes or epigenetic regulators. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/616681v1_ufig1.gif" ALT="Figure 1000"> View larger version (32K): org.highwire.dtl.DTLVardef@1314b69org.highwire.dtl.DTLVardef@14df9e1org.highwire.dtl.DTLVardef@505bddorg.highwire.dtl.DTLVardef@1bf3fab_HPS_FORMAT_FIGEXP M_FIG C_FIG