POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.
POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.
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DOI：
10.1016/j.canlet.2023.216444
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发表时间：
2023-10
期刊：
影响因子：
9.7
通讯作者：
Tiantian Jing;Xiaoli Xu;Chengsi Wu;Dian-Fang Wei;Lili Yuan;Yiwen Huang;Yizhen Liu;Boshi Wang-Boshi
中科院分区：
文献类型：
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作者：
Tiantian Jing;Xiaoli Xu;Chengsi Wu;Dian-Fang Wei;Lili Yuan;Yiwen Huang;Yizhen Liu;Boshi Wang-Boshi
胰腺腺泡细胞经历腺泡至导管化生（ADM），这是胰腺导管腺癌（PDAC）启动的必要过程。然而，POH 1（一种与几种类型的癌症相关的去泛素化酶）在ADM和PDAC中的调节作用尚不清楚。在这项研究中，我们研究了POH 1在ADM和PDAC使用小鼠模型的作用。我们的研究结果表明，胰腺特异性缺失Poh 1等位基因减弱ADM和损害胰腺癌的发生，提高小鼠的生存。POH1的机制是去泛素化并稳定MYC蛋白，从而增强ADM和PDAC。此外，POH1在PDAC样本中高度表达，临床证据证实了异常表达的POH1与PDAC患者的不良预后之间的正相关性。用特异性小分子抑制剂靶向POH1可显著减少胰腺肿瘤的形成，突出了POH1作为PDAC治疗的有希望的治疗靶点。总体而言，POH1介导的MYC去泛素化对于ADM和PDAC的发生至关重要，靶向POH1可能是PDAC治疗的有效策略，为PDAC靶向治疗提供了新的途径。
Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.