Histone H4K8 lactylation promotes glioblastoma progression by inducing NUPR1-mediated autophagosome‒lysosome fusion

TL;DR

This study shows that histone lactylation, specifically at H4K8, promotes glioblastoma growth by activating NUPR1, which enhances protective autophagy, and suggests targeting this pathway as a potential therapy.

Contribution

The study identifies the H4K8la-NUPR1 axis as a novel regulatory pathway in glioblastoma progression and proposes targeted therapeutic strategies.

Findings

Histone H4K8 lactylation is significantly elevated in glioblastoma cells.

NUPR1 activation by H4K8la promotes autophagosome-lysosome fusion and protective autophagy.

Pharmacological inhibition of NUPR1 with ZZW-115 reduces glioblastoma growth in models.

Abstract

Rationale: Glioblastoma (GBM), an aggressive malignant brain tumour associated with a dismal prognosis, is characterized by metabolic reprogramming that drives tumour progression, with the Warburg effect being a central contributor. This effect not only causes significant lactate buildup but also fuels lactylation, a novel post-translational modification implicated in the development of gliomas and various other cancers. Nevertheless, the exact molecular mechanisms by which lactylation promotes GBM progression remain largely elusive.

Methods: Lactylation levels in normal brain and GBM tissues were analysed using immunohistochemistry, immunofluorescence, and Western blotting. Glycolysis inhibitors and LDHA/LDHB knockdown were used to modulate histone lactylation in subsequent in vitro and in vivo experiments assessing GBM cell proliferation, invasion, and migration. CUT&Tag and RNA sequencing were used to identify H4K8la target genes, and NUPR1 expression was validated via ChIP‒qPCR and Western blotting. Autophagic flux was examined using transmission electron microscopy, EGFP-mCherry-LC3B probes, and LysoTracker staining. The therapeutic effects of NUPR1 inhibitor ZZW-115 were evaluated in both cellular and animal models.

Results: Histone lactylation, notably that of H4K8la, was markedly increased in GBM cells. Targeting lactate metabolism and lactylation levels attenuated GBM malignancy in vitro and in vivo. Genome-wide analysis revealed H4K8la enrichment at promoter regions, where it transcriptionally activated the autophagy regulator NUPR1. Functionally, NUPR1 enhanced protective autophagy via autophagosome‒lysosome fusion. Pharmacological inhibition of NUPR1 with ZZW-115 suppressed GBM growth by impairing autophagic flux, demonstrating therapeutic potential.

Conclusion: In summary, this study defines the functional and prognostic significance of histone lactylation in the progression of GBM. We identified the H4K8la-NUPR1 axis as a key regulatory pathway that mediates protective autophagy and developed targeted therapeutic strategies to disrupt this pathway. These findings provide novel insights into epigenetic regulation and targeted therapy for GBM.

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