Many erroneous noncoding transcripts in cancer cells can highly specifically regulate cancer-related genes and pathways

Abstract

Transcription and splicing errors in cancer cells generate erroneous transcripts. Since erroneous transcripts are degraded by the nonsense-mediated mRNA decay (NMD) pathway, whether they are junk or could be functional has been overlooked and understudied. We addressed this question by first performing a pan-cancer analysis and identified substantial erroneous noncoding transcripts (ENT) in cancers. Given that RNA/DNA binding domains (DBD) were predicted in ENTs, we deleted predicted DBDs in multiple ENTs in multiple cell lines, with RNA-sequencing and cell experiments before and after DBD deletion. DBD deletion caused significantly changed expression of ENTs target genes (whose promoter regions contain ENTs DNA binding sites, DBS) and changed cell migration and proliferation ability, indicating that many ENTs can transcriptionally regulate genes. Tightly coupled data analysis and experiments reveal that ENTs functions are highly cancer- and cellular-context specific, making ENTs a new class of safe and specific targets for noncoding RNA-based cancer therapeutics.