EIF3H Regulates ERK-Driven Oncogenic Signaling in Breast Cancer Metastasis

Breast cancer remains a leading cause of cancer-related mortality among women, with metastasis being the primary driver of poor prognosis. The ubiquitin-proteasome system (UPS) is a central regulator of protein homeostasis, and its dysregulation is associated with multiple cancers. Within this system, deubiquitinating enzymes (DUBs), which remove ubiquitin moieties from target proteins and thereby modulate their stability and function, have emerged as attractive therapeutic targets. Eukaryotic initiation factor 3 subunit H (EIF3H), a JAMM family DUB, is overexpressed in multiple cancers and implicated in stabilizing oncogenic proteins. Using clinical transcriptomic datasets, we identified EIF3H as significantly upregulated in breast invasive carcinoma, with high expression correlating with poor patient outcomes. Functional assays demonstrated that EIF3H overexpression enhances proliferation, migration, and invasion of breast cancer cells, whereas its knockdown suppresses these traits. Mechanistically, EIF3H physically interacts with and deubiquitinates phosphorylated ERK (pERK), preventing its degradation and sustaining MAPK pathway activation. This represents the first report of pERK as a direct EIF3H substrate, revealing a novel mechanism linking EIF3H to metastatic progression. Moreover, EIF3H-deficient cells display increased sensitivity to chemotherapeutic drugs, suggesting that pharmacological inhibition of EIF3H may simultaneously impair metastasis and improve therapeutic efficacy. Collectively, our findings identify EIF3H as a potential therapeutic target for combating metastatic breast cancer.