Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma  

作　　者：Li Peng Yanyi Jiang Hengxing Chen Yongqiang Wang Qiusheng Lan Shuiqin Chen Zhanwang Huang Jingyuan Zhang Duanqing Tian Yuntan Qiu Diankui Cai Jiangyun Peng Daning Lu Xiaoqing Yuan Xianzhu Yang Dong Yin 

机构地区：[1]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Guangdong-Hong Kong Joint Laboratory for RNA Medicine,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [2]Medical Research Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [3]Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230031,China [4]Department of Gastrointestinal Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [5]Department of Hepatobiliary Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [6]School of Biomedical Sciences and Engineering,South China University of Technology,Guangzhou International Campus,Guangzhou 511442,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2119-2136,共18页药学学报（英文版）

基　　金：This work was supported by grants from the National Key Research and Development Program of China(2021YFA0909300 to Dong Yin);the National Natural Science Foundation of China(82372617,81972658 and 81802812 to Li Peng,81803636 to Xiaoqing Yuan,82073067 and 81872140 to Dong Yin);Guangdong Basic and Applied Basic Research Foundation(2024B1515020090,2023A1515012683,2019A1515012114 and 2018A030313129 to Li Peng,2024A1515030038 to Xiaoqing Yuan,2021A0505030084 and 2019B020226003 to Dong Yin);Basic and Applied Basic Research of Guangzhou Municipal Basic Research Plan(2024A03J0845 and 2023A04J2098 to Li Peng);National Postdoctoral Program for Innovation Talents(grant no.BX20190395 to Li Peng);China Postdoctoral Science Foundation(grant no.2019M663254 to Li Peng);the Fundamental Research Funds for the Central Universities(grant no.20ykpy105 to Li Peng);the Science and Technology Planning Project of Guangdong Province(2023B1212060013 and 2020B1212030004).

摘　　要：Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

关 键 词：EHF AJUBA KRAS pathway Enhancer Core transcriptional regulatory circuitry Gastroesophageal adenocarcinoma Gastric adenocarcinoma Esophageal adenocarcinoma Transcription factor COACTIVATOR Lipid nanoparticles 

分 类 号：R563[医药卫生—呼吸系统]