Oncogene · 2025
ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zou Xiaoping, Nie Shuang, Cao Jing, Shi Mengyue, Schuck Kathleen, Shi Zhao, Zhang Lingling, Li Hongzhen, Sun Yifeng, Fang Chao, Hu Jingxiong, Niu Yiqi, Yu Yuanyuan, Zhang Zhiheng, Li Chao, Hu Mingyue, Wang Lei, Jiang Kuirong, Lu Zipeng, Akkan Jan, Raulefs Susanne, Kahlert Christoph, Roth Susanne, Herr Ingrid, Wan Yuan, Mihaljevic Andre, Qian Xuetian, Zhang Qi, Wang Maggie Haitian, Kleeff Jörg, Friess Helmut, Gu Zuguang, Michalski Christoph W, Shen Shanshan, Kong Bo
Аннотация
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.