FBP1 binds to the bromodomain of BRD4 to inhibit pancreatic cancer progression

Chong Yang; Shikai Zhu; Hongji Yang; Ping Fan; Zibo Meng; Jingyuan Zhao; Kun Zhang; Xin Jin

FBP1 binds to the bromodomain of BRD4 to inhibit pancreatic cancer progression

Am J Cancer Res. 2020 Feb 1;10(2):523-535. eCollection 2020.

Authors

Chong Yang¹, Shikai Zhu¹, Hongji Yang¹, Ping Fan², Zibo Meng³, Jingyuan Zhao³, Kun Zhang⁴, Xin Jin²

Affiliations

¹ Organ Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 610072, Sichuan, China.
² Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, Hubei, China.
³ Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, Hubei, China.
⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, Hubei, China.

PMID: 32195024
PMCID: PMC7061763

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour that is characteristically unresponsive to most chemotherapeutic regimens. Bromodomain and extra terminal domain (BET) inhibitors that specifically repress the function of BET family proteins, such as BRD4, are under evaluation in clinical trials for their activity in repressing cancer growth. However, resistance to BET inhibitors has hindered their further clinical application in pancreatic cancer. We previously reported that FBP1 contributes to the resistance to BET inhibitors, but the underlying mechanism of this resistance remains unclear. Herein, we demonstrate that FBP1 is a binding partner of BRD4 in pancreatic cancer cells. We reveal that FBP1 binds to the BD2 domain of BD4 in an acetylation-dependent manner. Moreover, we found that Tip60 and HDAC3 were key to the acetylation and de-acetylation of FBP1 at K110 and K113, which are critical for mediating FBP1-BRD4 binding in pancreatic cancer cells. Furthermore, our data indicate that FBP1 decreases the expression of genes downstream of BRD4 to inhibit pancreatic cancer cell progression. Our results, therefore, provide evidence of the novel anti-tumour effect of FBP1 via its blockade of BRD4 function in pancreatic cancer cells.

Keywords: Fructose-1,6-biphosphatase (FBP1); acetylation; bromodomain-containing protein 4 (BRD4); pancreatic cancer.