Blocking PSMD14-mediated E2F1/ERK/AKT signaling pathways suppresses the progression of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is the most aggressive subtype of thyroid cancer with few effective therapeutic strategies. Recent studies have identified the deubiquitinating enzyme (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a promising therapeutic target for multiple cancers; however, the role of PSMD14 in ATC remains largely unknown. Here, we found that PSMD14 was upregulated in ATC tissues and that its aberrant expression was negatively associated with the overall survival of patients with ATC. Functionally, PSMD14 promotes the proliferation and invasiveness of ATC cells, whereas the depletion of PSMD14 or PSMD14 inhibitor thiolutin (THL) inhibits the growth, invasiveness, and epithelial-mesenchymal transition ((EMT) of ATC cells. In addition, the cell cycle was arrested and apoptosis was increased in PSMD14-depleted ATC or ATC cells treated with THL in vitro. An in vivo assay indicated that THL exerted a potent inhibitory effect on ATC xenografts. Mechanistically, PSMD14 increased E2F1 stabilization by binding to and deubiquitinating E2F1. PSMD14-regulated E2F1 improved the activation of the ERK and AKT signaling pathways, which are instrumental in ATC tumorigenesis and progression. Overall, our findings reveal the oncogenic role of PSMD14 in ATC and provide a promising therapeutic target for the treatment of ATC.