| Autor: |
Siyuan Yan, Zhaonan Liu, Teng Wang, Yi Sui, Xiangsong Wu, Jiayi Shen, Peng Pu, Yang Yang, Sizhong Wu, Shimei Qiu, Ziyi Wang, Xiaoqing Jiang, Feiling Feng, Guoqiang Li, FaTao Liu, Chaoxian Zhao, Ke Liu, Jiayi Feng, Maolan Li, Kwan Man, Chaochen Wang, Yujie Tang, Yingbin Liu |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Advanced Science, Vol 11, Iss 47, Pp n/a-n/a (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2198-3844 |
| DOI: |
10.1002/advs.202406448 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Plný text