Editors' ChoiceCancer

Tumor’s loss is clinician’s gain

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Science Signaling  05 May 2020:
Vol. 13, Issue 630, eabc5604
DOI: 10.1126/scisignal.abc5604

A mutation in the epigenetic machinery creates a metabolic vulnerability in lung cancers.

The role of epigenetic dysregulation in cancer is increasingly evident. In lung cancers, loss-of-function mutations in histone methylation modifiers and other epigenetic modifiers are relatively common. Alam et al. found that loss-of-function mutations in the histone methyltransferase KMT2D (also called MLL4) create a metabolic vulnerability in lung cancers. In mouse models of lung adenocarcinoma, RNA sequencing and subsequent bioinformatic analysis of the tumors showed increased expression of genes associated with the glycolysis and oxidative phosphorylation (OXPHOS) pathways of cell metabolism, patterns that were corroborated in data from patient samples and in metabolite marker analysis in KMT2D-mutant LUAD cell line cultures. Inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) inhibited proliferation and induced cell death in KMT2D-mutant (as well as KMT2D- and KRAS-mutant) LUAD three-dimensional cultures.

Looking further at the mouse-model tumors, the authors noted that the loss of KMT2D decreased the amount of chromatin in enhancer and super-enhancer states (states that spatiotemporally activate gene expression), notably at the gene encoding the circadian rhythm–associated protein PER2. Molecular and cellular analyses indicated that KMT2D directly enhanced the expression of PER2, which in turn repressed that of glycolytic genes. These findings suggest that glycolytic inhibitors might be therapeutically effective in patients with KMT2D-deficient lung cancers.

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