DataVXAdvanced SciencePaper
journal article·2024-12Open access

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

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

Advanced Science· Volume 11· Issue 47
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Abstract

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.
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Research context

OpenAlex topics: Epigenetics and DNA Methylation · Cholangiocarcinoma and Gallbladder Cancer Studies · Genomics and Chromatin Dynamics

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Biliary‐Pancreatic Surgery Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200120 P. R. China

State Key Laboratory of Systems Medicine for Cancer,Shanghai Cancer Institute Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200127 P. R. China

Centre of Biomedical Systems and Informatics, ZJU‐UoE Institute Zhejiang University School of Medicine, International Campus Zhejiang University Haining 314400 P. R. China

Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education Shanghai Key Laboratory of Reproductive Medicine Department of Histoembryology, Genetics and Developmental Biology Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China

Department of General Surgery Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200092 P. R. China

School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 P. R. China

Department of Breast Surgery The Second Affiliated Hospital, Zhejiang University School of Medicine Zhejiang University Hangzhou 310009 P. R. China

School of Health Science and Engineering University of Shanghai for Science and Technology Shanghai 200093 P. R. China

Department of Biliary Tract Surgery I Shanghai Eastern Hepatobiliary Surgery Hospital Shanghai 200438 P. R. China

Department of Surgery School of Clinical Medicine LKS Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong SAR 999077 P. R. China

Shanghai Key Laboratory of Systems Regulation and Clinical Translation for Cancer Shanghai 200127 P. R. China

Department of General Surgery, Jiading Branch Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 201800 P. R. China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Shanghai Rising-Star Program · Chinese Universities Scientific Fund · Innovative Research Team of High-level Local University in Shanghai

References (66)

Show source-provided references
1. 10.3748/wjg.v21.i43.1221110.3748/wjg.v21.i43.12211 ↗
2. 10.1016/j.scib.2022.01.01110.1016/j.scib.2022.01.011 ↗
3. 10.1002/jso.2606610.1002/jso.26066 ↗
4. 10.1038/s41572-022-00398-y10.1038/s41572-022-00398-y ↗
5. 10.1186/s12885-021-08549-210.1186/s12885-021-08549-2 ↗
6. 10.1158/1078-0432.CCR-22-195410.1158/1078-0432.CCR-22-1954 ↗
7. 10.1038/s41392-020-00412-310.1038/s41392-020-00412-3 ↗
8. 10.1038/ng.303010.1038/ng.3030 ↗
9. 10.1016/j.jhep.2020.03.00710.1016/j.jhep.2020.03.007 ↗
10. 10.1158/2159-8290.CD-21-105910.1158/2159-8290.CD-21-1059 ↗
11. 10.1016/j.trecan.2020.03.00310.1016/j.trecan.2020.03.003 ↗
12. 10.1002/hep.3158510.1002/hep.31585 ↗
13. 10.1016/j.omto.2020.11.00710.1016/j.omto.2020.11.007 ↗
14. 10.1016/j.jhep.2018.01.00910.1016/j.jhep.2018.01.009 ↗
15. 10.1016/j.jhep.2012.01.01810.1016/j.jhep.2012.01.018 ↗
16. 10.1186/s11658-022-00398-610.1186/s11658-022-00398-6 ↗
17. 10.1038/nature0782910.1038/nature07829 ↗
18. 10.1038/nature0773010.1038/nature07730 ↗
19. 10.1016/j.cell.2013.09.05310.1016/j.cell.2013.09.053 ↗
20. 10.1016/j.ccell.2018.11.00110.1016/j.ccell.2018.11.001 ↗
21. 10.1016/j.cell.2017.07.00710.1016/j.cell.2017.07.007 ↗
22. 10.1101/gr.197590.11510.1101/gr.197590.115 ↗
23. 10.1038/s41388-020-01459-w10.1038/s41388-020-01459-w ↗
24. 10.1038/s41588-018-0191-z10.1038/s41588-018-0191-z ↗
25. 10.1038/s41591-018-0312-310.1038/s41591-018-0312-3 ↗
26. 10.1038/s41588-019-0534-410.1038/s41588-019-0534-4 ↗
27. 10.1136/gutjnl-2018-31603910.1136/gutjnl-2018-316039 ↗
28. 10.1038/s41392-020-00250-310.1038/s41392-020-00250-3 ↗
29. 10.1016/j.jhep.2021.06.02310.1016/j.jhep.2021.06.023 ↗
30. 10.1186/s13046-019-1237-510.1186/s13046-019-1237-5 ↗
31. 10.1242/dev.129.8.181910.1242/dev.129.8.1819 ↗
32. 10.1038/s41467-021-22139-710.1038/s41467-021-22139-7 ↗
33. 10.1016/j.devcel.2009.05.01210.1016/j.devcel.2009.05.012 ↗
34. 10.1242/dev.14751210.1242/dev.147512 ↗
35. 10.1007/s10238-014-0311-810.1007/s10238-014-0311-8 ↗
36. 10.1016/j.jhep.2020.11.03310.1016/j.jhep.2020.11.033 ↗
37. 10.1038/s41467-020-17880-410.1038/s41467-020-17880-4 ↗
38. 10.1016/j.semcancer.2019.03.00410.1016/j.semcancer.2019.03.004 ↗
39. 10.1016/j.ydbio.2015.05.01210.1016/j.ydbio.2015.05.012 ↗
40. 10.1016/j.jcmgh.2021.01.00910.1016/j.jcmgh.2021.01.009 ↗
41. 10.1038/ajg.2011.30510.1038/ajg.2011.305 ↗
42. 10.1002/dvdy.2190010.1002/dvdy.21900 ↗
43. 10.1016/j.biocel.2010.06.02010.1016/j.biocel.2010.06.020 ↗
44. 10.1007/s13277-015-4728-910.1007/s13277-015-4728-9 ↗
45. 10.1016/j.tranon.2023.10173210.1016/j.tranon.2023.101732 ↗
46. 10.1016/j.cellsig.2024.11104210.1016/j.cellsig.2024.111042 ↗
47. 10.3389/fonc.2020.0082310.3389/fonc.2020.00823 ↗
48. 10.1007/s11684-023-1008-810.1007/s11684-023-1008-8 ↗
49. 10.1016/j.jbc.2022.10273510.1016/j.jbc.2022.102735 ↗
50. 10.1038/nrc265710.1038/nrc2657 ↗
51. 10.1038/s41421-022-00445-810.1038/s41421-022-00445-8 ↗
52. 10.1016/j.pharmthera.2022.10822910.1016/j.pharmthera.2022.108229 ↗
53. 10.1016/j.biocel.2009.10.01710.1016/j.biocel.2009.10.017 ↗
54. 10.1016/j.bbamcr.2012.06.02710.1016/j.bbamcr.2012.06.027 ↗
55. 10.1126/sciadv.abe084910.1126/sciadv.abe0849 ↗
56. 10.1101/gad.117110410.1101/gad.1171104 ↗
57. 10.1095/biolreprod.115.13127610.1095/biolreprod.115.131276 ↗
58. 10.1038/s41388-022-02313-x10.1038/s41388-022-02313-x ↗
59. 10.1016/j.molcel.2015.09.00210.1016/j.molcel.2015.09.002 ↗
60. 10.1016/j.jhep.2020.11.03310.1016/j.jhep.2020.11.033 ↗
61. 10.1038/s41586-019-1186-310.1038/s41586-019-1186-3 ↗
62. 10.1016/j.cell.2015.08.06310.1016/j.cell.2015.08.063 ↗
63. 10.1038/s41388-019-0701-110.1038/s41388-019-0701-1 ↗
64. 10.1007/s13577-021-00492-510.1007/s13577-021-00492-5 ↗
65. 10.21037/tcr.2020.02.0410.21037/tcr.2020.02.04 ↗
66. 10.3389/fonc.2022.99408710.3389/fonc.2022.994087 ↗