Reprogramming of valine metabolism mediated by abnormally low ALDH6A1 expression promotes invasive metastasis of gastric cancer.

Abstract

Metastasis in gastric cancer requires metabolic reprogramming, but its key drivers remain unclear. Using a CRISPR-Cas9 metabolic knockout screen integrated with patient transcriptomes, we identified the mitochondrial enzyme ALDH6A1 as an anti-invasive factor. <i>ALDH6A1</i> down-regulation blocked the terminal step of valine catabolism and caused intracellular accumulation of methylmalonic acid (MMA). MMA competitively occupied the α-ketoglutarate (α-KG) cofactor pocket of the histone demethylase KDM5C, suppressing its activity and increasing H3K4 dimethylation (H3K4me2) at promoters of invasion-related genes, including <i>ANGPT2</i> (angiopoietin-2) and <i>MMP7</i> (matrix metalloproteinase 7). This epigenetic reprogramming promoted gastric cancer liver metastasis in mice. Pharmacologic ALDH6A1 activation with Alda-1 or systemic MMA clearance with l-carnitine lowered H3K4me2, dampened the invasive program, and reduced metastatic burden. These findings identify the ALDH6A1-MMA axis as a targetable metabolic-epigenetic pathway in gastric cancer metastasis.