ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-08-08 DOI:10.1038/s41388-025-03530-w

Xiaoping Zou, Shuang Nie, Jing Cao, Mengyue Shi, Kathleen Schuck, Zhao Shi, Lingling Zhang, Hongzhen Li, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Yuanyuan Yu, Zhiheng Zhang, Chao Li, Mingyue Hu, Lei Wang, Kuirong Jiang, Zipeng Lu, Jan Akkan, Susanne Raulefs, Christoph Kahlert, Susanne Roth, Ingrid Herr, Yuan Wan, Andre Mihaljevic, Xuetian Qian, Qi Zhang, Maggie Haitian Wang, Jörg Kleeff, Helmut Friess, Zuguang Gu, Christoph W. Michalski, Shanshan Shen, Bo Kong

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Abstract

The basal-like transcriptional subtype of pancreatic ductal adenocarcinoma (PDAC) is linked to therapy resistance and poor prognosis. The cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) is a critical enzyme in acetaldehyde metabolism, but the interconnection to the basal-like subtype is poorly understood. Here, we identified ALDH1A3 as a key gene, which correlates with reduced survival and increased tumor growth. Functional studies revealed interaction of ALDH1A3 with genes like FAM3C, MCC, PMEPA1, and IRS2, forming a network driving PDAC progression. Chromatin profiling showed that ALDH1A3 affects acetylation of histone 3, mediating AP-1 activity, particularly via FOS family members, activating oncogenic pathways such as MAPK and TNF signaling. RUNX2 emerged as a therapeutic target within this network, as its knockdown disrupted MAPK signaling and reduced tumor growth. These findings emphasize the role of ALDH1A3 in linking nuclear metabolic-epigenetic programming in basal-like PDAC, highlighting it as a promising therapeutic target for novel treatment strategies.

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ALDH1A3通过AP-1/RUNX2增强子网络促进侵袭性基底样胰腺癌。

胰腺导管腺癌（PDAC）的基底样转录亚型与治疗抵抗和预后不良有关。癌症干细胞标志物乙醛脱氢酶1A3 （ALDH1A3）是乙醛代谢的关键酶，但与基底样亚型的相互联系尚不清楚。在这里，我们发现ALDH1A3是一个关键基因，它与降低生存率和增加肿瘤生长有关。功能研究显示ALDH1A3与FAM3C、MCC、PMEPA1和IRS2等基因相互作用，形成驱动PDAC进展的网络。染色质分析显示，ALDH1A3影响组蛋白3的乙酰化，介导AP-1活性，特别是通过FOS家族成员，激活MAPK和TNF信号通路等致癌途径。RUNX2在这个网络中作为一个治疗靶点出现，因为它的敲低破坏了MAPK信号并降低了肿瘤生长。这些发现强调了ALDH1A3在连接基底样PDAC的核代谢-表观遗传编程中的作用，突出了它作为新治疗策略的有希望的治疗靶点。

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

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.