Hypoxia Silences an Invasion-Braking Gene in Oral Cancer via a Nuclear LOX-H1.5 Pathway

Hypoxia appears to strip oral squamous cell carcinoma cells of an important brake on invasion by silencing a gene called DAG1, according to a new study published in the Journal of Translational Medicine. The work, led by Yuyang Zhang, Jun Chen and colleagues with senior author Wei Han, describes a previously underappreciated epigenetic route by which low oxygen conditions help tumor cells detach from the basement membrane and push toward the most aggressive patterns of invasion, known as worst pattern of invasion (WPOI) 4–5, a marker of poor prognosis in patients with oral squamous cell carcinoma.

The researchers combined several lines of evidence to build their case. Immunohistochemistry, qRT-PCR and western blotting showed that DAG1 expression was reduced in hypoxic conditions at both the messenger RNA and protein levels. Functionally, this loss impaired cell-matrix adhesion and promoted invasion of oral cancer cells in vitro, consistent with DAG1 acting as an invasion-suppressive extracellular matrix anchor whose loss correlates with aggressive WPOI patterns and worse outcomes.

To uncover the mechanism, the team performed quantitative global crotonylome profiling, a technique that maps chemical crotonylation marks across the proteome. Under hypoxia, they observed a prominent loss of crotonylation on linker histone H1 variants. Specifically, histone H1.5 was enriched at regulatory regions of the DAG1 gene, and its crotonylation proved essential for maintaining DAG1 transcription. When that mark was removed through decrotonylation, DAG1 expression fell.

The study also identified an upstream regulator of this process: the enzyme lysyl oxidase, or LOX, which the authors found acting within the nucleus to drive H1.5 decrotonylation. Silencing LOX restored H1.5 crotonylation, promoted DAG1 expression and impaired the invasiveness induced by hypoxia. LOX levels also correlated with DAG1 status, tying the enzyme into the same regulatory axis.

The findings were extended into animal models. In orthotopic tongue xenograft mice, depletion of DAG1 enhanced local invasion of oral squamous cell carcinoma tumors, while pharmacological inhibition of LOX attenuated tumor progression and invasion. Taken together, the authors propose a model in which hypoxia activates a nuclear LOX–H1.5 decrotonylation axis that represses DAG1 and licenses invasive progression, and they suggest this axis represents a clinically relevant vulnerability that could be targeted therapeutically. As with all preclinical work, the pharmacological results come from mouse xenograft models and in vitro assays, and translating LOX targeting into patient care will require further validation.

Subject of Research: How hypoxia-driven epigenetic repression of DAG1 promotes invasion in oral squamous cell carcinoma

Article Title: Hypoxia drives a nuclear LOX-H1.5 decrotonylation axis that represses DAG1 and licenses invasive progression in oral squamous cell carcinoma

Article References: Zhang, Y., Chen, J., Zhang, Y., Wang, Z., Yu, J., Wu, X., Zhang, J., Xie, D., Yin, X., & Han, W. (2026). Hypoxia drives a nuclear LOX-H1.5 decrotonylation axis that represses DAG1 and licenses invasive progression in oral squamous cell carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09150-6

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09150-6

Keywords: oral squamous cell carcinoma, hypoxia, lysyl oxidase, histone H1.5, decrotonylation, DAG1, epigenetics, crotonylome, tumor invasion, WPOI, orthotopic xenograft model, drives