灭活的母亲针对十五肢麻痹同源物 (SMAD) 4 的抑制因子显着影响胰腺导管腺癌 (PDAC) 的癌症发展。然而，smad4 缺失对 PDAC 耐药性的影响很大程度上尚未确定。在本研究中，我们报道 SMAD4 的缺失赋予 PDAC 细胞通过上调组蛋白赖氨酸脱甲基酶、赖氨酸特异性脱甲基酶 5B（KDM5B，也称为 JARID1B 或 PLU1）产生耐药性的能力。在 PDAC 中发现 KDM5B 上调，与 PDAC 患者的不良预后和复发相关。 KDM5B上调可促进PDAC肿瘤恶性，即体外和体内癌细胞的干性和耐药性，而KDM5B敲除则会产生相反的作用。从机制上讲，Smad4 介导的 KDM5B 上调的丧失可通过抑制椎间盘大同源物 1 (DLG1) 来促进耐药性，从而促进 YAP 的核转位以诱导从头脂肪生成。此外，m6A 去甲基酶 FTO 通过维持 KDM5B mRNA 稳定性参与 KDM5B 的上调。总的来说，本研究表明，在 Smad4 缺失的情况下，FTO 介导的 KDM5B 稳定会激活 DLG1/YAP1 通路，通过重编程 PDAC 中的脂质积累来促进肿瘤发生。我们的研究证实KDM5B-DLG1-YAP1通路轴在PDAC的发生和进展中起着至关重要的作用，KDM5B有望成为PDAC的治疗靶点。 KDM5B-DLG1-YAP通路轴调节PDAC对吉西他滨(GEM)耐药的示意图。在 SMAD4 缺失的 PDAC 细胞中，FTO 介导的 KDM5B 稳定和上调通过直接靶向 DLG1 促进 YAP1 易位至细胞核以诱导从头脂肪生成 (DNL)，从而促进耐药性。© 2024。作者。

Inactivated suppressor of mothers against decapentaplegic homolog (SMAD) 4 significantly affects cancer development in pancreatic ductal adenocarcinoma (PDAC). However, the contribution of smad4 loss to drug resistance in PDAC is largely undetermined. In the present study, we reported that the loss of SMAD4 endows PDAC cells the ability to drug resistance through upregulating histone lysine demethylase, Lysine-Specific Demethylase 5B (KDM5B, also known as JARID1B or PLU1). Upregulated KDM5B was found in PDAC, associated with poor prognosis and recurrence of PDAC patients. Upregulated KDM5B promotes PDAC tumor malignancy, i.e. cancer cells stemness and drug resistance in vitro and in vivo, while KDM5B knockout exerts opposite effects. Mechanistically, loss of Smad4-mediated upregulation of KDM5B promotes drug resistance through inhibiting the discs-large homolog 1 (DLG1), thereby facilitating nuclear translocation of YAP to induce de novo lipogenesis. Moreover, m6A demethylase FTO is involved in the upregulation of KDM5B by maintaining KDM5B mRNA stability. Collectively, the present study suggested FTO-mediated KDM5B stabilization in the context of loss of Smad4 activate DLG1/YAP1 pathway to promote tumorigenesis by reprogramming lipid accumulation in PDAC. Our study confirmed that the KDM5B-DLG1-YAP1 pathway axis plays a crucial role in the genesis and progression of PDAC, and KDM5B was expected to become a target for the treatment of PDAC. The schematic diagram of KDM5B-DLG1-YAP pathway axis in regulating drug resistance of PDAC to gemcitabine (GEM). In the context of SMAD4 loss PDAC cells, FTO-mediated stabilization and upregulation of KDM5B promotes drug resistance through directly targeting DLG1 to promote YAP1 translocation to nucleus to induce de novo lipogenesis (DNL).© 2024. The Author(s).