The long non-coding RNA, CyKILRb, augments oncogenic phenotypes via induction of PIK3R2 and activation of the PI3K/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 PI3K/AKT signaling pathway to block downstream tumor suppressors. In particular, downregulation of CyKILRb induced the loss of PIK3R2, an activator of PI3K, 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, PI3K or AKT attenuated CyKILRb-induced cell proliferation and clonogenic survival. CyKILRb negatively regulated CyKILRa expression, which was blocked by inhibition of either PI3K or AKT. PIK3R2 ectopic expression overcame the cellular effects of CyKILRb downregulation, but not PI3K or AKT inhibition orienting the signaling pathway from CyKILRb[->]{uparrow}PIK3R2[->]PI3K[->]AKT[->]{downarrow}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.