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PTEN regulates expression of its pseudogene in glioblastoma cells in DNA methylation-dependent manner

Tatyana F Kovalenko1, Bhupender Yadav2, Ksenia S Anufrieva3

  • 1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.

Biochimie
|August 24, 2023
PubMed

Insights

In glioblastoma, PTEN protein regulates lncPTENP1-S expression via DNA methylation. This long non-coding RNA promotes cancer by increasing stem cell markers and decreasing cell adhesion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Glioblastoma (GBM) is an aggressive brain cancer linked to PTEN tumor suppressor dysfunction.
  • PTEN pseudogene (PTENP1) produces lncPTENP1-S, with interconnected regulation to PTEN.
  • The precise molecular interplay between PTEN and PTENP1 in GBM remains largely unknown.

Purpose of the Study:

  • To investigate the methylation status of PTEN and PTENP1 promoter CpG islands in GBM.
  • To elucidate the regulatory mechanism between PTEN and lncPTENP1-S.
  • To determine the functional role of lncPTENP1-S in GBM pathogenesis.

Main Methods:

  • Analysis of CpG island methylation in PTEN and PTENP1 promoters in patient-derived GBM neurospheres.
  • Targeted methylation and demethylation of PTENP1 CpGI.
  • PTEN protein binding assays to the PTENP1 promoter.
  • Assessment of lncPTENP1-S effects on PTEN mRNA levels.
  • Evaluation of lncPTENP1-S function on cancer stem cell markers and cell adhesion.

Main Results:

  • Increased PTEN methylation correlated with decreased PTEN mRNA levels.
  • PTENP1 promoter methylation showed an inverse correlation with PTEN mRNA levels.
  • DNA methylation of PTENP1 CpGI modulated lncPTENP1-S expression, dependent on PTEN protein presence.
  • PTEN protein binding to a demethylated PTENP1 promoter inhibited lncPTENP1-S expression.
  • lncPTENP1-S did not affect PTEN mRNA levels, suggesting PTENP1 is a downstream target.
  • lncPTENP1-S promoted GBM by upregulating cancer stem cell markers and decreasing cell adhesion.

Conclusions:

  • PTEN protein directly regulates lncPTENP1-S expression through epigenetic mechanisms involving PTENP1 promoter methylation.
  • PTENP1 acts as a downstream target of PTEN in GBM cells.
  • lncPTENP1-S plays a pro-oncogenic role in GBM, contributing to its aggressive phenotype.
Keywords:
CpG islandDNA methylationGlioblastomaPTENPTENP1lncPTENP1

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