Lysosomal homeostasis maintained by DCPS-mediated SLC4A7 splicing confers dependency in glioblastoma stem cells

Abstract

Abstract Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which lack therapeutic targets. Here, we identify RNA decapping enzyme DCPS as an essential regulator of GSC maintenance and GBM progression. Epigenetically regulated DCPS expression levels correlate with GBM stemness and poor patient survival. Targeting DCPS impairs GSC stemness and extends survival of GBM-bearing mouse models. Mechanistically, DCPS controls the alternative splicing landscape of GSCs independently of its decapping enzyme activity. DCPS ensures mRNA stability of SLC4A7 by suppressing exon skipping and nonsense-mediated decay. Inhibition of the DCPS-SLC4A7 axis leads to intracellular acidification, lysosomal membrane permeabilization, and subsequent pyroptosis. SLC4A7 is overexpressed in GBM patients and is essential for GSC stemness. Collectively, our findings uncover a DCPS-SLC4A7 axis that maintains GBM stemness and malignancy, linking epigenetic regulation, RNA biology, and lysosomal homeostasis and highlighting a promising therapeutic vulnerability in GBM.