BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression

• Published in: Oncogene 2022-01, Vol.41 (3), p.347-360
• Main Authors: Wu, Qiong, Liu, Fangfang, Ge, Mengmeng, Laster, Kyle Vaughn, Wei, Lixiao, Du, Ruijuan, Jiang, Ming, Zhang, Jing, Zhi, Yafei, Jin, Guoguo, Zhao, Simin, Kim, Dong Joon, Dong, Zigang, Liu, Kangdong
• Format: Article
• Language: English
• Subjects: 13/105; 13/109; 13/89; 38/91; 45/90; 631/337/572; 631/67/395; 64/60; 82/47; Animals; Apoptosis; Cell Biology; Cell growth; Cell Line, Tumor; Cell proliferation; Chromatin; Chromosomal Proteins, Non-Histone - metabolism; Epigenetics; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - mortality; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Human Genetics; Humans; Internal Medicine; Male; Medical prognosis; Medicine; Medicine & Public Health; Mice; Mice, Nude; Molecular modelling; Nuclear Proteins - metabolism; Oncogenes; Oncology; Prognosis; Proteomics; Squamous cell carcinoma; Survival Analysis; Transcription; Transcription Factors - metabolism; Transcriptomics; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-02099-4

The low survival rate of esophageal squamous cell carcinoma patients is primarily attributed to technical limitations and a lack of insight regarding the molecular mechanisms contributing to its progression. Alterations in epigenetic modulators are critical to cancer development and prognosis. BRD4, a chromatin reader protein, plays an essential role in regulating oncogene expression. Here, we investigated the contributing role of BRD4 and its related mechanisms in the context of ESCC tumor progression. Our observations showed that BRD4 transcript and protein expression levels are significantly increased in ESCC patient tissues. Genetic or pharmacological inhibition of BRD4 suppressed ESCC cell proliferation in vitro and in vivo. Proteomic and transcriptomic analyses were subsequently used to deduce the potential targets of BRD4. Mechanistic studies showed that RCC2 is a downstream target of BRD4. Inhibition of either BRD4 or RCC2 resulted in decreased ESCC cell proliferation. The BRD4-TP73 interaction facilitated the binding of BRD4 complex to the promoter region of RCC2, and subsequently modulated RCC2 transcription. Furthermore, targeting BRD4 with inhibitors significantly decreased tumor volume in ESCC PDX models, indicating that BRD4 expression may contribute to tumor progression. Collectively, these findings suggest that BRD4 inhibition could be a promising strategy to treat ESCC by downregulating RCC2.