Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer
Gallbladder cancer (GBC) is a highly aggressive malignancy lacking clinically available targeted therapeutic agents. Super-enhancers (SEs) are crucial epigenetic cis-regulatory elements whose extensive reprogramming drives aberrant transcription in cancers. To study SE in GBC, the genomic distribution of H3K27ac is profiled in multiple GBC tissue and cell line samples to establish the SE landscape and its associated core regulatory circuitry (CRC). The biliary lineage factor SOX9 and Wnt pathway effector TCF7L2, two master transcription factor (TF) candidates identified by CRC analysis, are verified to co-occupy each other's SE region, forming a mutually autoregulatory loop to drive oncogenic SE reprogramming in a subset of GBC. The SOX9/TCF7L2 double-high GBC cells are highly dependent on the two TFs and enriched of SE-associated gene signatures related to stemness, ErbB and Wnt pathways. Patients with more such GBC cells exhibited significantly worse prognosis. Furthermore, SOX9/TCF7L2 double-high GBC preclinical models are found to be susceptible to SE-targeted CDK7 inhibition therapy in vitro and in vivo. Together, this study provides novel insights into the epigenetic mechanisms underlying the oncogenesis of a subset of GBCs with poorer prognosis and illustrates promising prognostic stratification and therapeutic strategies for treating those GBC patients in future clinical trials.
Authors
- Yi Sui (ORCID: https://orcid.org/0000-0002-2898-7877)
- Chaoxian Zhao (ORCID: https://orcid.org/0000-0002-7126-0841)
- Shimei Qiu
- Fatao Liu (ORCID: https://orcid.org/0000-0002-5183-9418)
- Xiaoqing Jiang (ORCID: https://orcid.org/0000-0002-6339-8912)
- Siyuan Yan (ORCID: https://orcid.org/0000-0002-4127-904X)
- Peng Pu (ORCID: https://orcid.org/0000-0003-0502-0513)
- Jiayi Shen (ORCID: https://orcid.org/0000-0003-4157-7175)
- Chaochen Wang (ORCID: https://orcid.org/0000-0003-2346-2884)
- Yujie Tang (ORCID: https://orcid.org/0000-0001-7647-5780)
- Chiman Kwan (ORCID: https://orcid.org/0000-0002-4341-0769)
- Maolan Li (ORCID: https://orcid.org/0000-0002-4147-3715)
- Ke Liu (ORCID: https://orcid.org/0000-0002-2652-1774)
- Guoqiang Li (ORCID: https://orcid.org/0000-0001-9729-4911)
- Yang Yang (ORCID: https://orcid.org/0000-0001-7432-4735)
- Ziyi Wang (ORCID: https://orcid.org/0000-0002-1334-7287)
- Yingbin Liu (ORCID: https://orcid.org/0000-0001-6110-0185)
- Jiayi Feng (ORCID: https://orcid.org/0009-0009-4405-9518)
- Teng Wang (ORCID: https://orcid.org/0009-0005-3259-088X)
- Sizhong Wu
- Zhaonan Liu (ORCID: https://orcid.org/0000-0002-8561-6861)
- Xiangsong Wu
- Feiling Feng
Institutions
- University of Shanghai for Science and Technology (CN)
- Chinese University of Hong Kong (HK)
- Second Military Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- XinHua Hospital (CN)
- Shanghai Cancer Institute (CN)
- Eastern Hepatobiliary Surgery Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1002/advs.202406448
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- Shanghai Rising-Star Program
- Renji Hospital
- Chinese Universities Scientific Fund
- School of Medicine, Shanghai Jiao Tong University
- National Key Research and Development Program of China