Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-09 DOI:10.1126/sciadv.adr3173

Yuanhang Yu, Jin Hu, Wenwen Wang, Hao Lei, Zihan Xi, Peiyi Zhang, Ende Zhao, Chong Lu, Hengyu Chen, Chunping Liu, Lei Li

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Abstract

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.

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靶向PSMD14联合花生四烯酸通过FADS1 m6A修饰诱导三阴性乳腺癌的合成致死

去泛素化的失调对癌症的生长至关重要。然而，26S蛋白酶体非atp酶调控亚基14 （PSMD14）在三阴性乳腺癌（TNBC）进展中的作用仍有待确定。功能增益和功能丧失实验表明，沉默PSMD14在体外和体内均可显著减弱TNBC细胞的生长、侵袭和转移。PSMD14过表达产生相反的结果。机制上，PSMD14降低SF3B4蛋白上k63连接的泛素化，使SF3B4蛋白脱泛素，稳定SF3B4蛋白。然后，SF3B4/HNRNPC复合物结合到FADS1 mRNA上，通过HNRNPC识别的FADS1 mRNA上的m6A位点，促进靶mRNA的外显子包合，从而上调FADS1的表达，激活Akt/mTOR信号通路。外源性花生四烯酸补充联合PSMD14敲低诱导合成致死性，这在TNBC类器官（PDO）和TNBC患者源异种移植（PDX）小鼠模型中得到进一步证实。总的来说，我们的研究结果揭示了PSMD14在TNBC进展中的致癌作用，这表明了一种潜在的生物标志物和铁凋亡介导的TNBC治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.