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Long Non-Coding RNAs Contribute to Glucose Starvation-Induced Dedifferentiation in Lung Adenocarcinoma

Aparamita Pandey1, Pasquale Saggese1,2, Adriana Soto1

  • 1Division of Pulmonary Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA.

Biomolecules
|November 27, 2025
PubMed

Insights

Nutrient deprivation triggers tumor dedifferentiation via epigenetic changes. Glucose restriction causes histone and RNA hypermethylation, upregulating long non-coding RNAs like LINC00662, which drives aggressive tumor phenotypes.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Nutrient deprivation induces tumor dedifferentiation and aggressive phenotypes.
  • Glucose starvation triggers epigenetic alterations, including histone methylation, via alpha-ketoglutarate (α-KG) deficits.
  • α-KG-dependent histone demethylase deficiency leads to EZH2-mediated H3K27 hypermethylation, a key driver of starvation-induced dedifferentiation.

Purpose of the Study:

  • To investigate epitranscriptomic changes induced by glucose restriction.
  • To identify specific long non-coding RNAs (lncRNAs) involved in the epigenetic response to low glucose.
  • To elucidate the role of RNA methylation in EZH2 recruitment and tumor dedifferentiation.

Main Methods:

  • Analysis of epigenetic and epitranscriptomic modifications under glucose deprivation.
  • Identification of key lncRNAs and their regulatory mechanisms.
  • Investigation of RNA demethylase FTO activity and its impact on lncRNA methylation.
  • Assessment of EZH2 recruitment to target gene promoters.

Main Results:

  • Glucose restriction induces epitranscriptomic changes, including select long non-coding RNA (lncRNA) hypermethylation.
  • Reduced activity of RNA demethylase FTO leads to lncRNA upregulation under glucose deprivation.
  • LINC00662 was identified as a crucial lncRNA for EZH2 recruitment to target gene promoters in low glucose conditions.
  • RNA methylation of lncRNAs represents a parallel epigenetic mechanism converging on EZH2.

Conclusions:

  • Glucose restriction impacts both histone and RNA methylation, contributing to tumor dedifferentiation.
  • lncRNA methylation, exemplified by LINC00662, is a significant component of the epigenetic response to nutrient stress.
  • These findings reveal a coordinated epigenetic and epitranscriptomic regulation of EZH2 activity in response to glucose deprivation, driving aggressive tumor phenotypes.
Keywords:
EZH2FTOdedifferentiationepitranscriptomicsglucose starvationlong noncoding RNAlung adenocarcinoma

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