2. Academic Validation
  3. BRD9 promotes the progression of gallbladder cancer via CST1 upregulation and interaction with FOXP1 through the PI3K/AKT pathway and represents a therapeutic target

BRD9 promotes the progression of gallbladder cancer via CST1 upregulation and interaction with FOXP1 through the PI3K/AKT pathway and represents a therapeutic target

  • Gene Ther. 2024 Sep 21. doi: 10.1038/s41434-024-00488-4.
Jing Qiang # 1 2,  Cheng Zhao # 1 2,  Liu-Qing Shi # 1 2,  Si-Rui Sun # 3,  Hua-Kai Wang 1 2,  Shi-Lei Liu 1 2,  Zi-Yi Yang 1 2,  Ping Dong 4 5,  Shan-Shan Xiang 6 7,  Jian-Dong Wang 8 9,  Yi-Jun Shu 10 11
Affiliations

Affiliations

  • 1 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China.
  • 2 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai, 200092, China.
  • 3 The Hockaday School, Dallas, TX, USA.
  • 4 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. dongping@xinhuamed.com.cn.
  • 5 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai, 200092, China. dongping@xinhuamed.com.cn.
  • 6 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. xiangshanshan1989@163.com.
  • 7 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai, 200092, China. xiangshanshan1989@163.com.
  • 8 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. wangjiandong@xinhuamed.com.cn.
  • 9 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai, 200092, China. wangjiandong@xinhuamed.com.cn.
  • 10 Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China. shuyijun19881125@163.com.
  • 11 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China, No. 1665 Kongjiang Road, Shanghai, 200092, China. shuyijun19881125@163.com.
  • # Contributed equally.
PMID: 39306629 DOI: 10.1038/s41434-024-00488-4
Abstract

Gallbladder Cancer (GBC) is highly aggressive and has poor prognosis, with most patients only diagnosed at an advanced stage. Furthermore, treatment options are limited, and their effect is unsatisfactory. Bromodomain-containing protein (BRD) is an epigenetic regulator that plays a carcinogenic role in several tumors, including squamous cell lung Cancer, acute myeloid leukemia, synovial sarcoma, and malignant rhabdomyosarcoma. However, the expression, biological function, and molecular mechanisms of action of BRD9 in GBC are still unknown. Kaplan-Meier analysis, qRT-PCR, and analysis of clinical features were used to assess the clinical significance of BRD9 in GBC. Cell Counting Kit-8 and colony formation assays were performed to determine the effects of BRD9 on cell growth. The functional role of BRD9 in GBC was explored using qRT-PCR, western blotting, siRNA, and CHIP-qPCR. mRNA Sequencing was performed to explore the underlying mechanisms of BRD9, and a nude mouse model of GBC was established to explore the anti-tumor effects of the BRD9 Inhibitor I-BRD9 in vivo. BRD9 expression was elevated in GBC tissues compared with adjacent non-tumor tissues, and high BRD9 expression was associated with poor prognosis in patients with GBC. BRD9 knockdown by siRNA significantly decreased cell growth. Targeting BRD9 with I-BRD9 inhibited the proliferation of GBC cells without significant toxic effects. Additionally, I-BRD9 treatment suppressed CST1 expression in GBC cell lines, thereby inhibiting the PI3K-AKT pathway. The transcription factor FOXP1 was found to interact with BRD9 to regulate CST1 expression. Collectively, these results suggest that BRD9 may be a promising biomarker and therapeutic target for GBC.

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