Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer

• Published in: Advanced science 2024-12, Vol.11 (47), p.e2406448-n/a
• Main Authors: Yan, Siyuan, Liu, Zhaonan, Wang, Teng, Sui, Yi, Wu, Xiangsong, Shen, Jiayi, Pu, Peng, Yang, Yang, Wu, Sizhong, Qiu, Shimei, Wang, Ziyi, Jiang, Xiaoqing, Feng, Feiling, Li, Guoqiang, Liu, FaTao, Zhao, Chaoxian, Liu, Ke, Feng, Jiayi, Li, Maolan, Man, Kwan, Wang, Chaochen, Tang, Yujie, Liu, Yingbin
• Format: Article
• Language: English
• Subjects: Animals; Cancer therapies; Cell Line, Tumor; core regulatory circuitry; Correlation analysis; Datasets; Disease Models, Animal; DNA methylation; Enhancer Elements, Genetic - genetics; Epigenetics; Gallbladder cancer; Gallbladder Neoplasms - genetics; Gallbladder Neoplasms - metabolism; Gallbladder Neoplasms - pathology; Gene Expression Regulation, Neoplastic - genetics; Genes; Genomes; Humans; Medical prognosis; Mice; Mutation; Pathogenesis; SOX9; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; super‐enhancer; TCF7L2; Transcription Factor 7-Like 2 Protein - genetics; Transcription Factor 7-Like 2 Protein - metabolism; transcription‐targeted CDK7 inhibition therapy; Tumorigenesis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202406448

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. This study explores epigenetic mechanisms underlying oncogenesis of gallbladder cancer (GBC), revealing SOX9 and TCF7L2 can form a core regulatory circuitry (CRC) to drive oncogenic SE reprogramming and subsequent transcriptional activation of critical malignant genes. The SOX9/TCF7L2 double‐high GBCs exhibit worse prognosis and are susceptible to CDK7‐targeted transcription inhibition therapy.