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

TL;DR

This study shows that glucose starvation in lung cancer cells causes changes in RNA methylation, which helps cancer cells become more aggressive.

Contribution

The study reveals that RNA methylation of lncRNAs like LINC00662 is a new mechanism in glucose starvation-induced dedifferentiation.

Findings

Glucose restriction causes hypermethylation of specific long non-coding RNAs due to reduced FTO activity.

LINC00662 is essential for recruiting EZH2 to gene promoters under low glucose conditions.

RNA methylation of lncRNAs acts as a parallel mechanism to histone methylation in starvation-induced dedifferentiation.

Abstract

Nutrient deprivation causes dedifferentiation in solid tumors, driving an aggressive phenotype. We previously showed that glucose starvation-induced dedifferentiation is driven by epigenetic changes induced by a deficit of alpha-ketoglutarate (α-KG). Deficient activity of α-KG-dependent histone demethylases leads to unbalanced hypermethylation of histone 3 on lysine 27 (H3K27) by methyltransferase EZH2. H3K27 hypermethylation is a key mechanism of starvation-induced dedifferentiation. Here, we investigate a new aspect of this mechanism and show that epitranscriptomic changes are also induced by glucose restriction. Specifically, hypermethylation of select long non-coding RNAs leads to their upregulation under glucose deprivation as a consequence of reduced activity of the RNA demethylase FTO. We identified LINC00662 as an lncRNA required for EZH2 recruitment to target gene promoters induced by low glucose. These findings characterize the epigenetic response to glucose restriction beyond histone methylation, revealing that RNA methylation of lncRNAs such as LINC00662 represents a parallel mechanism converging on EZH2.

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