Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer
Menée à l'aide de lignées cellulaires, d'organoïdes, d'échantillons tumoraux et de modèles murins de cancer mammaire triple négatif, cette étude met en évidence le rôle de la protéine PSMD14 dans la progression tumorale, démontre qu'une supplémentation en acide arachidonique en combinaison avec la suppression de l'expression de PSMD14 favorise la mort des cellules cancéreuses puis identifie le mécanisme d'action
Dysregulation of deubiquitination is essential for cancer growth. However, the role of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain- and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis of TNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m6A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy for TNBC. Targeting PSMD14 reduces FADS1-mediated production of unsaturated fatty acids and attenuates susceptibility to ferroptosis.
Science Advances , article en libre accès 2025