RNA splicing variants of the novel long non-coding RNA, CyKILR, possess divergent biological functions in non-small cell lung cancer

Abstract

ABSTRACTThe CDKN2A gene, responsible for encoding the tumor suppressors p16(INK4A) and p14(ARF), is frequently inactivated in non-small cell lung cancer (NSCLC). In this study, an uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) on chromosome 19p13.12 was found to be overexpressed in NSCLC cells with an active CDKN2A gene. This lncRNA, namedCyclin-DependentKinaseInhibitor 2A-regulatedlncRNA (CyKILR), also correlated with the STK11 gene-coded tumor suppressor Liver kinase B1 (LKB1). CyKILR displayed two splice variants, CyKILRa (with exon 3) and CyKILRb (without exon 3), which are synergistically regulated by CDKN2A and STK11 as knockdown of both tumor suppressor genes led to a significant loss of exon 3 inclusion in mature CyKILR RNA. CyKILRa localized to the nucleus, and its downregulation using antisense RNA oligonucleotides enhanced cellular proliferation, migration, clonogenic survival, and tumor incidence. In contrast, CyKILRb localized to the cytoplasm, and downregulation of CyKILRb using siRNA reduced cell proliferation, migration, clonogenic survival, and tumor incidence. Transcriptomics analyses revealed enhancement of apoptotic pathways with concomitant suppression of key cell cycle pathways by CyKILRa demonstrating its tumor-suppressive role, while CyKILRb inhibited tumor suppressor microRNAs, indicating an oncogenic nature. These findings elucidate the intricate roles of lncRNAs in cell signaling and tumorigenesis.