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Loss of p53-inducible long non-coding RNA LINC01021 increases chemosensitivity

Markus Kaller1, Ursula Götz1, Heiko Hermeking1,2,3

  • 1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.

Oncotarget
|December 22, 2017
PubMed

Insights

Long non-coding RNA LINC01021, a p53 target, is upregulated in colorectal cancer. Its deletion enhances chemotherapy sensitivity, indicating a role in DNA damage response and potential as a prognostic marker in colorectal cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • The long non-coding RNA LINC01021 was previously identified as a direct target of the tumor suppressor protein p53.
  • Colorectal cancer (CRC) exhibits complex genetic alterations, including dysregulation of p53 and non-coding RNAs.

Purpose of the Study:

  • To investigate the role of LINC01021 in colorectal cancer (CRC) and its relationship with p53.
  • To explore the therapeutic implications of targeting LINC01021 in CRC treatment.

Main Methods:

  • Analysis of LINC01021 expression in CRC cell lines upon p53-activating treatments.
  • CRISPR/Cas9-mediated deletion of the LINC01021 promoter region and siRNA-mediated knockdown of LINC01021.
  • Assessment of CRC cell sensitivity to chemotherapeutic drugs (doxorubicin, 5-FU).
  • Correlation analysis of LINC01021 expression with p53 signatures and patient survival data in CRC samples.

Main Results:

  • LINC01021 is upregulated in CRC cell lines following p53 activation, with its regulatory elements originating from endogenous retrovirus 1 (ERV1) sequences.
  • Deletion or knockdown of LINC01021 significantly increased CRC cell sensitivity to doxorubicin and 5-FU, highlighting its role in the p53-mediated DNA damage response.
  • LINC01021 expression positively correlated with wild-type p53 signatures in CRC patients, and its elevated levels were observed in primary tumors, particularly in the mesenchymal CMS4 subtype.
  • Low LINC01021 expression in CMS4 tumors was associated with poorer patient survival.

Conclusions:

  • LINC01021 functions as an integral component of the p53-mediated response to genotoxic stress in colorectal cancer.
  • The findings suggest that LINC01021 may serve as a prognostic biomarker for colorectal cancer, especially within specific molecular subtypes.
  • The evolutionary selection for ERV1-derived p53-inducible lncRNAs highlights their conserved role in cellular stress responses.
Keywords:
LINC01021chemosensitivitycolorectal cancerp53tumor suppression

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