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

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

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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 transcrip-tional 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 strat-egy.

EHFAJUBAKRAS pathwayEnhancerCore transcriptional regulatory circuitryGastroesophageal adenocarcinomaGastric adenocarcinomaEsophageal adenocarcinomaTranscription factorCoactivatorLipid nanoparticles

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

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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

Medical Research Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China

Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230031,China

Department of Gastrointestinal Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China

Department of Hepatobiliary Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China

School of Biomedical Sciences and Engineering,South China University of Technology,Guangzhou International Campus,Guangzhou 511442,China

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国家重点研发计划国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Guangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationBasic and Applied Basic Research of Guangzhou Municipal Basic Research PlanBasic and Applied Basic Research of Guangzhou Municipal Basic Research PlanNational Postdoctoral Program for Innovation Talents中国博士后科学基金中央高校基本科研业务费专项广东省科技计划广东省科技计划

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2024

10.1016/j.apsb.2024.02.025

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(5)
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