TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma
TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma
SUMMARY Transcriptional network is controlled by master transcription factors (TFs) and cis-regulatory elements through interacting with target sequences and recruiting epigenetic regulators. By integration of enhancer profiling and chromatin accessibility, we establish super-enhancer (SE) mediated core regulatory circuitry (CRC) for esophageal squamous cell carcinoma (ESCC) and identify tumor cells-dependent CRC TFs-TP63, SOX2 and KLF5. They preferentially co-occupy SE loci and form a positive interconnected auto-regulatory loop through SEs to orchestrate chromatin and transcriptional programming. SE-associated oncogene-ALDH3A1 is identified as a novel CRC target contributing to ESCC viability. Using circular chromosome conformation capture sequencing (4C-seq) and CRISPR/Cas9 genome editing, the direct interaction between TP63 promoter and functional enhancers which is mediated by CRC TFs is identified. Deletion of each enhancer decreases expression of CRC TFs and impairs cell viability, phenocopying the knockdown of each CRC TF. Targeting epigenetic regulation by inhibition of either the BET bromodomain or HDAC disrupts the CRC program and its dependent global epigenetic modification, consequently suppressing ESCC tumor growth. Importantly, combination of both compounds result in synergistic anti-tumor effect. Graphical Abstractbiorxiv;825372v1/UFIG1F1ufig1 HIGHLIGHTSSuper-enhancers mediated transcriptional regulatory circuitry is established for ESCCTP63, SOX2 and KLF5 as CRC TFs co-localize super-enhancer loci to orchestrate chromatin accessibility and transcriptional dysregulationComplex interaction between functional enhancers and TP63 promoter is mediated by CRC TFsALDH3A1 is a key downstream target of ESCC CRC and is essential for ESCC cell survivalBET degrader-ARV-771 and HDAC inhibitor-Romidepsin synergistically inhibit ESCC tumor growth
Jiang Yuan、Fullwood Melissa J.、Guan Xin-Yuan、Jiang Yan-Yi、Han Lin、Hazawa Masaharu、Li YanYu、Aswad Luay、Lin De-Chen、Koeffler H. Phillip、Lin Ruby Yu-Tong、Jeitany Maya、Dakle Pushkar、Kanojia Deepika、Kaur Harvinder、Xie Jian-Jun、Mayakonda Anand、Li Chun-Quan、Deng Jian-Wen、Zhang Ying、Xu Liang
Cancer Science Institute of Singapore, National University of Singapore||Department of Medicine, Cedars-Sinai Medical CenterCancer Science Institute of Singapore, National University of Singapore||School of Biological Sciences, Nanyang Technological UniversityDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong KongCancer Science Institute of Singapore, National University of Singapore||Department of Medicine, Cedars-Sinai Medical CenterCancer Science Institute of Singapore, National University of SingaporeCell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa UniversitySchool of Medical Informatics, Daqing Campus, Harbin Medical UniversityCancer Science Institute of Singapore, National University of Singapore||School of Biological Sciences, Nanyang Technological UniversityDepartment of Medicine, Cedars-Sinai Medical CenterCancer Science Institute of Singapore, National University of Singapore||Department of Medicine, Cedars-Sinai Medical Center||National University Cancer Institute, National University Hospital SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeDepartment of Biochemistry and Molecular Biology, Medical College of Shantou UniversityCancer Science Institute of Singapore, National University of SingaporeSchool of Medical Informatics, Daqing Campus, Harbin Medical UniversityCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of SingaporeCancer Science Institute of Singapore, National University of Singapore
肿瘤学基础医学分子生物学
Jiang Yuan,Fullwood Melissa J.,Guan Xin-Yuan,Jiang Yan-Yi,Han Lin,Hazawa Masaharu,Li YanYu,Aswad Luay,Lin De-Chen,Koeffler H. Phillip,Lin Ruby Yu-Tong,Jeitany Maya,Dakle Pushkar,Kanojia Deepika,Kaur Harvinder,Xie Jian-Jun,Mayakonda Anand,Li Chun-Quan,Deng Jian-Wen,Zhang Ying,Xu Liang.TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/825372.点此复制
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