The long non-coding RNA, CyKILRb, augments oncogenic phenotypes via induction of PIK3R2 and activation of the PI ₃ K/AKT axis

Our laboratory recently identified a novel long noncoding RNA termed CyKILR that has two splice variants with distinct cellular localizations and opposing roles in tumorigenesis. The cytoplasmic variant, CyKILRb (exon 3 exclusion), promotes tumorigenesis, whereas the nuclear variant, CyKILRa (exon 3 inclusion), functions as a tumor suppressor. In this study, the molecular mechanism of the tumorigenic role of CyKILRb was characterized. Specifically, deep RNA sequencing analysis revealed that CyKILRb regulated the PI ₃ K/AKT signaling pathway to block downstream tumor suppressors. In particular, downregulation of CyKILRb induced the loss of PIK3R2, an activator of PI ₃ K, as well as RPS6KB2 and GNB2, two implicated tumor promotors, with a concomitant increase in the tumor suppressors, CDKN1A (p21) and CDKN1B (p27). In contrast, CyKILRb ectopic expression produced the opposite effect, and suppression of either PIK3R2, PI ₃ K or AKT attenuated CyKILRb-induced cell proliferation and clonogenic survival. CyKILRb negatively regulated CyKILRa expression, which was blocked by inhibition of either PI ₃ K or AKT. PIK3R2 ectopic expression overcame the cellular effects of CyKILRb downregulation, but not PI ₃ K or AKT inhibition orienting the signaling pathway from CyKILRb→↑PIK3R2→PI3K→AKT→↓CyKILRa→enhanced oncogenicity. These findings highlight the critical role of CyKILRb in tumorigenesis and define a novel feed-forward regulatory mechanism linked to alternative RNA splicing.