HEXB promotes tumor progression of glioblastoma through the HIF1α-CA9 pathway as a therapeutic approach

A major challenge in GBM treatment is the paucity of patient-specific therapeutic targets, underscoring the need to identify actionable vulnerabilities that drive GBM progression. Here, through integrative proteomic and transcriptomic profiling of matched GBM tissues and non-tumor tissues adjacent to the tumor from individual patients, we identified the β-subunit of β-hexosaminidase, encoded by HEXB, as a previously underappreciated mediator of GBM progression.

Inhibition of HEXB markedly attenuated GBM cell proliferation and tumorigenicity. Mechanistically, HEXB interacted with HIF1α, prevented its ubiquitin-mediated degradation, and promoted its nuclear translocation, thereby enhancing the transcriptional upregulation of CA9, a hypoxia-associated enzyme implicated in glioma progression. Guided by these findings, brain-targeted nanocapsule delivery of HEXB-directed siRNA exerted therapeutic efficacy, as evidenced by robust suppression of GBM cell proliferation and tumor growth, as well as prolonged survival in mice bearing GBM xenografts.