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BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression

Oncogene volume 41, pages 347–360 (2022)Cite this article

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Abstract

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.

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Fig. 1: BRD4 is highly expressed in ESCC.
Fig. 2: BRD4 promotes cell proliferation in ESCC.
Fig. 3: BRD4 upregulates RCC2 expression.
Fig. 4: BRD4 regulates promoter activity of RCC2 through TP73.
Fig. 5: RCC2 is highly expressed in ESCC and promotes cell proliferation in ESCC.
Fig. 6: Anti-tumor activity of BRD4 inhibitors (+)-JQ1 and OTX015 in ESCC PDX models and RCC2 expression was assessed in several ESCC PDX model cases.
Fig. 7: A schematic model illustrating the findings of this paper.

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Acknowledgements

This research was funded by the National Natural Science Foundations of China (Grant no. 81872335), National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (No. 2018ZX09711002) and Central Plains Science and Technology Innovation Leading Talents (KL). We thank all members of our team for critical input and suggestions.

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  1. These authors contributed equally: Qiong Wu, Fangfang Liu

Authors and Affiliations

  1. The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China

    Qiong Wu, Fangfang Liu, Ruijuan Du, Jing Zhang, Yafei Zhi, Dong Joon Kim, Zigang Dong & Kangdong Liu

  2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China

    Qiong Wu, Fangfang Liu, Mengmeng Ge, Kyle Vaughn Laster, Lixiao Wei, Ruijuan Du, Ming Jiang, Jing Zhang, Yafei Zhi, Guoguo Jin, Simin Zhao, Dong Joon Kim, Zigang Dong & Kangdong Liu

  3. The Henan Luoyang Orthopedic Hospital, Zhengzhou, 450000, Henan, China

    Guoguo Jin

  4. Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China

    Simin Zhao

  5. State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China

    Zigang Dong & Kangdong Liu

  6. Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China

    Zigang Dong & Kangdong Liu

  7. Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China

    Kangdong Liu

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Contributions

QW designed and performed the most of experiments and the data analysis; FL, MG and LW helped in animal experimentation; KVL took charge of bioinformatics analyses; QW and KVL prepared and revised the manuscript; RD, MJ, GJ, and SZ provided technique supports; JZ and YZ helped perform in vitro assays. DJK and ZD supervise the overall experimental design. KL designed and supervised the study; All authors read and approved the final manuscript.

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Correspondence to Dong Joon Kim, Zigang Dong or Kangdong Liu.

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This study was approved by the Ethics Committee of Zhengzhou University. All the animal experiments performed in this study were approved by the Institutional Animal Care and Use Committee of Zhengzhou University.

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Wu, Q., Liu, F., Ge, M. et al. BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression. Oncogene 41, 347–360 (2022). https://doi.org/10.1038/s41388-021-02099-4

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