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Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Although the hypoxia-inducible factor 1A (HIF1A) pathway is crucial in HCC progression, its regulatory mechanisms remain unclear as mutations in its primary regulator, von Hippel-Lindau tumor suppressor (VHL), are rare in HCC. We aimed to elucidate the role of proliferation and apoptosis adaptor protein 15 (PEA15), identified through proteomic analysis, as a regulator of the VHL/HIF1A pathway and a therapeutic target in HCC.

Methods

Proteomic and genomic analyses of over 1,000 HCC samples were conducted, identifying PEA15 amplification. Functional validation involved in vitro and in vivo assays, including gene knockdown, ectopic expression, and antisense oligonucleotide (ASO) therapy in xenograft models. Protein interactions were assessed using immunoprecipitation and ubiquitination assays.

Results

We identified 3 clinically distinct HCC subtypes and found that PEA15 was selectively amplified and highly expressed in the mesenchymal (MES) subtype, which exhibited the poorest prognosis. PEA15 acted as a regulator of the VHL/HIF1A pathway and a key oncogene in HCC. The amplification of PEA15 was significantly associated with the poor survival of HCC patients. Moreover, by interacting with the β-domain of VHL, PEA15 promoted HCC cell proliferation and migration by inhibiting VHL's interaction with the VHL/elongin C (ELOC)/elongin B (ELOB)/cullin 2 (CUL2) E3 ligase complex, destabilizing the complex and consequently activating HIF1A. Importantly, pharmacologically inhibiting PEA15 using PEA15 ASO drugs attenuated tumor burden and restored VHL function in a xenograft mouse model.

Conclusions

This study identified PEA15 as a potential oncogene in HCC, regulating the VHL/HIF1A axis and driving tumor progression. Targeting PEA15 using ASOs offers a promising therapeutic strategy for HCC, particularly in the MES subtype. These findings provide a basis for further exploration of PEA15-targeted therapies to improve HCC outcomes.