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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Experimental & Clinical Cancer Research 1/2018

FBP1 loss contributes to BET inhibitors resistance by undermining c-Myc expression in pancreatic ductal adenocarcinoma

Zeitschrift:
Journal of Experimental & Clinical Cancer Research > Ausgabe 1/2018
Autoren:
Bo Wang, Ping Fan, Jingyuan Zhao, Heyu Wu, Xin Jin, Heshui Wu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13046-018-0888-y) contains supplementary material, which is available to authorized users.
Bo Wang and Ping Fan contributed equally to this work.

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide. BET inhibitors display anti-tumor activity in pancreatic cancer, however the cells often develop resistance after a long-term treatment and the underlying molecular basis is not fully understood.

Methods

Drug screening assay in Fructose-1, 6-biphosphatase (FBP1) knockdown or overexpressing pancreatic cancer cells was performed. Tumor cell motility, FBP1 protein and mRNA changes were investigated after BET inhibitors treatment. The interaction between TRIM28 and FBP1 after BET inhibitors treatment was examined by Co-immunoprecipitation (IP) and GST pull-down. The relationship between FBP1 and c-Myc was examined by western blot, RT-qPCR and immunohistochemistry (IHC).

Results

The expression of FBP1 protein increased the sensitivity of pancreatic cancer cells to JQ1. Furthermore, we showed that JQ1 stabilized FBP1 protein level by disrupting the interaction between FBP1 and TRIM28 in pancreatic cancer cells. Moreover, we demonstrated that FBP1 promoted c-Myc degradation through disrupting the ERK-c-Myc axis.

Conclusions

FBP1 modulates the sensitivity of pancreatic cancer cells to BET inhibitors by decreasing the expression of c-Myc. These findings highlight FBP1 could be used as a therapeutic niche for patient-tailored therapies.
Zusatzmaterial
Additional file 1: Figure S1. BRD2, BRD3 or BRD4 make no effect on the expression of FBP1. Table S2. Sequences for shRNAs. (ZIP 272 kb)
13046_2018_888_MOESM1_ESM.zip
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