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

Xiujie Xie1, H Patrick Macknight1, Amy L Lu1

  • 1Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, VA 22903, USA.

Molecular Therapy. Nucleic Acids
|January 14, 2025
PubMed

Insights

A novel long non-coding RNA, CyKILR, is overexpressed in non-small cell lung cancer (NSCLC) and exhibits distinct tumor-suppressive (CyKILRa) and oncogenic (CyKILRb) functions, regulated by CDKN2A and STK11 tumor suppressors.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Non-coding RNA Research

Background:

  • The CDKN2A gene, encoding tumor suppressors p16(INK4A) and p14(ARF), is frequently inactivated in non-small cell lung cancer (NSCLC).
  • Understanding the role of non-coding RNAs in cancer development is crucial for identifying new therapeutic targets.

Purpose of the Study:

  • To characterize a novel long non-coding RNA (lncRNA) overexpressed in NSCLC cells with active CDKN2A.
  • To elucidate the functional roles of different splice variants of this lncRNA in tumorigenesis.

Main Methods:

  • Identification and naming of the lncRNA (CyKILR) and its splice variants (CyKILRa, CyKILRb).
  • Analysis of CyKILR regulation by CDKN2A and STK11 tumor suppressor genes.
  • Subcellular localization studies (nucleus for CyKILRa, cytoplasm for CyKILRb).
  • Functional assays following knockdown of CyKILR variants (proliferation, migration, survival, tumor incidence).
  • Transcriptomics to determine pathway involvement (apoptosis, cell cycle, miRNA regulation).

Main Results:

  • CyKILR is overexpressed in NSCLC with wild-type CDKN2A and correlates with wild-type STK11.
  • CDKN2A and STK11 cooperatively regulate CyKILR splicing, specifically exon 3 inclusion.
  • CyKILRa (nuclear) knockdown enhanced proliferation, migration, survival, and tumor incidence.
  • CyKILRb (cytoplasmic) knockdown reduced proliferation, migration, survival, and tumor incidence.
  • CyKILRa promoted apoptosis and suppressed cell-cycle pathways; CyKILRb inhibited tumor suppressor miRNAs.

Conclusions:

  • CyKILR exhibits dual roles in NSCLC, with CyKILRa acting as a tumor suppressor and CyKILRb as an oncogene.
  • The expression and function of CyKILR variants are intricately linked to CDKN2A and STK11 status.
  • This study reveals novel insights into lncRNA involvement in cancer cell signaling and tumorigenesis.
Keywords:
CDKN2ALKB1MT: Non-coding RNAsRNA splicingSTK11antisense oligonucleotideslong non-coding RNAsnon-small cell lung cancers

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